Methods of making bempedoic acid and compositions of the same

ABSTRACT

The invention provides methods of preparing 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid and methods of making a pharmaceutical material comprising a purified amount of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid. Also provided are compositions and pharmaceutical materials including a purified amount of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid as well as methods of treating various diseases and conditions using the compositions and pharmaceutical materials.

CROSS-REFERENCE

This application claims the benefit of and priority to U.S. PatentApplication No. 62/864,873, filed on Jun. 21, 2019, the entire contentsof which are incorporated by reference herein.

BACKGROUND

The development of robust, cost-effective and efficient manufacturingmethods for the production of pharmaceutically active compounds withdesired yield and purity remains a significant challenge. Bempedoic acid(8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a compoundunder development for the treatment of a wide variety of diseasesincluding liver disorders and cardiovascular disease. Accordingly, aprocess for synthesizing bempedoic acid(8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is desired,whereby the product has purity and impurity profiles required byregulatory agencies for the production of a commercializable drugproduct.

SUMMARY

The inventors have discovered an efficient process for producing highpurity bempedoic acid, as well as highly pure, stable forms of bempedoicacid suitable for use as an active pharmaceutical ingredient.

In one aspect, the invention provides methods of preparing a compound offormula (V):

or a pharmaceutically acceptable salt thereof. The compound of formula(V), or a pharmaceutically acceptable salt thereof, can be of highpurity. Accordingly, in certain embodiments, the invention providesmethods of preparing a pharmaceutical material comprising a compound offormula (V), or a pharmaceutically acceptable salt thereof, where thepharmaceutical material includes the compound of formula (V), or apharmaceutically acceptable salt thereof, in an amount greater than99.0% by weight based on the total weight of the pharmaceuticalmaterial.

In various embodiments of the invention, the method generally comprises:

(a) contacting ethyl isobutyrate with a substituted 5-chloropentane inthe presence of a first base to form a compound of formula (I):

wherein the substituted 5-chloropentane is selected from the groupconsisting of 1-bromo-5-chloropentane and 1-iodo-5-chloropentane;

(b) contacting the compound of formula (I) with a salt of formula[M]⁺[X]⁻ to form a compound of formula (II):

wherein [M]⁺ is selected from the group consisting of Li⁺, Na⁺ and K⁺,wherein [X]⁻ is selected from the group consisting of Br⁻ and I⁻;

(c) contacting the compound of formula (II) with toluenesulfonylmethylisocyanide in the presence of a second base to form a firstintermediate, and contacting the first intermediate with an acid to forma compound of formula (IV):

and

(d) contacting the compound of formula (IV) with a reducing agent toform a second intermediate, and contacting the second intermediate witha hydrolyzing base to form a compound of formula (V), or apharmaceutically acceptable salt thereof.

In certain embodiments of the invention, the method comprises:

(a) contacting 1-bromo-5-chloropentane with about 1 to about 1.21 molarequivalents of ethyl isobutyrate in the presence of lithiumdiisopropylamide at a temperature in the range of about −20° C. to about0° C. to form a compound of formula (I):

(b) contacting the compound of formula (I) with about 1.1 molarequivalents of sodium iodide in 2-butanone at a temperature in the rangeof about 78° C. to about 82° C. to form a compound of formula (IIa):

(c) contacting the compound of formula (IIa) with toluenesulfonylmethylisocyanide in the presence of sodium tert-pentoxide in dimethylacetamideat a temperature in the range of about −20° C. to about 10° C. to forman intermediate, and contacting the intermediate with an acid at atemperature in the range of about −10° C. to about 35° C. to form acompound of formula (IV):

and

(d) contacting the compound of formula (IV) with about 0.35 molarequivalents of sodium borohydride to form a second intermediate, andcontacting the second intermediate with sodium hydroxide in a solutionto form a compound of formula (V).

In certain embodiments of the invention, the method further comprises:

(e) purifying the compound of formula (V) to provide a pharmaceuticalmaterial comprising a purified amount of the compound of formula (V).

In certain embodiments of the invention, purifying the compound offormula (V) comprises:

(f) adjusting the pH of the solution comprising the compound of formula(V) to about 6;

(g) extracting the compound of formula (V) from the solution usingmethyl tert-butyl ether to provide a methyl tert-butyl ether solutioncomprising the compound of formula (V);

(h) exchanging the methyl tert-butyl ether of the methyl tert-butylether solution with ethyl acetate to provide an ethyl acetate solutioncomprising the compound of formula (V);

(i) filtering the ethyl acetate solution comprising the compound offormula (V) through silica gel;

(j) crystallizing the compound of formula (V) using ethyl acetate andwater to provide a crystalline form of the compound of formula (V); and

(k) recrystallizing the crystalline form of the compound of formula (V)using ethyl acetate and water to provide a pharmaceutical materialcomprising a purified amount of the compound of formula (V).

In another aspect, the invention provides high purity or purifiedbempedoic acid, or a pharmaceutically acceptable salt thereof. Forexample, described herein are pharmaceutical materials comprising acompound of formula (V):

or a pharmaceutically acceptable salt thereof, wherein thepharmaceutical material comprises the compound of formula (V), or apharmaceutically acceptable salt thereof, in an amount greater than99.0% by weight based on the total weight of the pharmaceuticalmaterial.

In various embodiments, the pharmaceutical material comprises acrystalline form of the compound of formula (V), or a pharmaceuticallyacceptable salt thereof. In some embodiments, the pharmaceuticalmaterial comprises the compound of formula (V) in an amount greater than99.0% by weight based on the total weight of the pharmaceuticalmaterial.

In another aspect, the invention provides pharmaceutical compositions orformulations including high purity bempedoic acid, or a pharmaceuticallyacceptable salt thereof, such as the pharmaceutical materials describedherein. For example, a pharmaceutical composition can include apharmaceutical material of the invention (e.g., a pharmaceuticalmaterial comprising the compound of formula (V), or a pharmaceuticallyacceptable salt thereof, in an amount greater than 99.0% by weight basedon the total weight of the pharmaceutical material); and apharmaceutically acceptable excipient. In some embodiments, apharmaceutical composition can include a therapeutically effectiveamount of a pharmaceutical material of the invention; and apharmaceutically acceptable excipient. In certain embodiments, thepharmaceutical composition comprises a crystalline form of the compoundof formula (V), or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable excipient.

Purified bempedoic acid, or a pharmaceutically acceptable salt thereof;a crystalline form of bempedoic acid, or a pharmaceutically acceptablesalt thereof; a pharmaceutical material of the invention (e.g., apharmaceutical material comprising the compound of formula (V), or apharmaceutically acceptable salt thereof, in an amount greater than99.0% by weight based on the total weight of the pharmaceuticalmaterial); or a pharmaceutical composition of the invention can be usedin treating the various conditions and diseases described herein. Forexample, the methods of treatment can include inhibiting adenosinetriphosphate citrate lyase (ACL), inhibiting cholesterol synthesis,and/or suppressing fatty acid biosynthesis. In some embodiments, thecondition or disease can be hyperlipidemia such as primaryhyperlipidemia and the methods include treating hyperlipidemia such asprimary hyperlipidemia. In some embodiments, the disease can becardiovascular disease and the methods include treating cardiovasculardisease. In various embodiments, the methods of treatment can includeimproving or lowering low density lipid cholesterol (LDL-C), non-highdensity lipid cholesterol (non-HDL-C), total serum cholesterol (TC),apolipoprotein B (apoB), and/or high sensitivity C-reactive protein(hsCRP).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an exemplary reaction scheme of the invention for thesynthesis of bempedoic acid (i.e., a compound of formula (V)) asdescribed in Example 1, which reaction scheme includes the synthesis ofa pharmaceutical material comprising the compound of formula (V) in anamount greater than 99.0% by weight based on the total weight of thepharmaceutical material.

FIG. 2 is an exemplary ¹H-NMR spectrum of the compound of formula (V).

FIG. 3 is an exemplary ¹³C-NMR spectrum of the compound of formula (V).

FIG. 4 is an X-ray powder diffraction pattern of the crystalline form ofthe compound of formula (V), as further described in Example 1.

FIG. 5 is an overlay of differential scanning calorimetry (DSC) andthermogravimetric analysis (TGA) curves of the crystalline form of thecompound of formula (V), as further described in Example 1.

FIG. 6 is a water sorption isotherm of the crystalline form of thecompound of formula (V).

DETAILED DESCRIPTION OF THE INVENTION

It has now been discovered that bempedoic acid, includingpharmaceutically acceptable salts thereof, can be prepared with highpurity and/or in bulk quantities. In various embodiments, a crystallineform of bempedoic acid, or a pharmaceutically acceptable salt thereof,is provided.

The methods for preparing bempedoic acid described herein can provide apharmaceutical material containing a high level or amount of bempedoicacid, or a pharmaceutically acceptable salt thereof, in part, due to thecontrol of the formation of hard-to-remove impurities during thesynthetic process.

In addition, a pharmaceutical material with a high purity crystallineform of bempedoic acid, or a pharmaceutically acceptable salt thereof,is provided, for example, where the pharmaceutical material comprisesthe crystalline form of bempedoic acid, or a pharmaceutically acceptablesalt thereof, and wherein the pharmaceutical material comprisesbemepedoic acid, or a pharmaceutically acceptable salt thereof, in anamount greater than 99.0% by weight based on the total weight of thepharmaceutical material.

I. Definitions

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. The abbreviations used hereinhave their conventional meaning within the chemical and biological arts.The chemical structures and formulae set forth herein are constructedaccording to the standard rules of chemical valency known in thechemical arts.

Throughout the description, where compositions and kits are described ashaving, including, or comprising specific components, or where processesand methods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions andkits of the present invention that consist essentially of, or consistof, the recited components, and that there are processes and methodsaccording to the present invention that consist essentially of, orconsist of, the recited processing steps.

In the application, where an element or component is said to be includedin and/or selected from a list of recited elements or components, itshould be understood that the element or component can be any one of therecited elements or components, or the element or component can beselected from a group consisting of two or more of the recited elementsor components.

Further, it should be understood that elements and/or features of acomposition or a method described herein can be combined in a variety ofways without departing from the spirit and scope of the presentinvention, whether explicit or implicit herein. For example, wherereference is made to a particular compound, that compound can be used invarious embodiments of compositions of the present invention and/or inmethods of the present invention, unless otherwise understood from thecontext. In other words, within this application, embodiments have beendescribed and depicted in a way that enables a clear and conciseapplication to be written and drawn, but it is intended and will beappreciated that embodiments may be variously combined or separatedwithout parting from the present teachings and invention(s). Forexample, it will be appreciated that all features described and depictedherein can be applicable to all aspects of the invention(s) describedand depicted herein.

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle, unless the context is inappropriate. By way of example, “anelement” means one element or more than one element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

It should be understood that the expression “at least one of” includesindividually each of the recited objects after the expression and thevarious combinations of two or more of the recited objects unlessotherwise understood from the context and use. The expression “and/or”in connection with three or more recited objects should be understood tohave the same meaning unless otherwise understood from the context.

The use of the term “include,” “includes,” “including,” “have,” “has,”“having,” “contain,” “contains,” or “containing,” including grammaticalequivalents thereof, should be understood generally as open-ended andnon-limiting, for example, not excluding additional unrecited elementsor steps, unless otherwise specifically stated or understood from thecontext.

Where the use of the term “about” is before a quantitative value, thepresent invention also includes the specific quantitative value itself,unless specifically stated otherwise. As used herein, the term “about”refers to a ±10% variation from the nominal value unless otherwiseindicated or inferred from the context.

Where a molecular weight is provided and not an absolute value, forexample, of a polymer, then the molecular weight should be understood tobe an average molecule weight, unless otherwise stated or understoodfrom the context.

It should be understood that the order of steps or order for performingcertain actions is immaterial so long as the present invention remainoperable. Moreover, two or more steps or actions may be conductedsimultaneously.

At various places in the present specification, variable or parametersare disclosed in groups or in ranges. It is specifically intended thatthe description include each and every individual subcombination of themembers of such groups and ranges. For example, an integer in the rangeof 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and40, and an integer in the range of 1 to 20 is specifically intended toindividually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, and 20.

The use of any and all examples, or exemplary language herein, forexample, “such as” or “including,” is intended merely to illustratebetter the present invention and does not pose a limitation on the scopeof the invention unless claimed. No language in the specification shouldbe construed as indicating any non-claimed element as essential to thepractice of the present invention.

As a general matter, compositions specifying a percentage are by weightunless otherwise specified. Further, if a variable is not accompanied bya definition, then the previous definition of the variable controls.

As used herein, “pharmaceutically acceptable salt” refers to any salt ofan acidic or a basic group that may be present in a compound of thepresent invention, which salt is compatible with pharmaceuticaladministration. For example, one or both of the carboxylic acid groupsof bempedoic acid can be transformed to pharmaceutically acceptablesalt(s).

As is known to those of skill in the art, “salts” of compounds may bederived from inorganic or organic acids and bases. Examples of acidsinclude, but are not limited to, hydrochloric, hydrobromic, sulfuric,nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic,salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric,methanesulfonic, ethanesulfonic, formic, benzoic, malonic,naphthalene-2-sulfonic and benzenesulfonic acid. Other acids, such asoxalic, while not in themselves pharmaceutically acceptable, may beemployed in the preparation of salts useful as intermediates inobtaining the compounds described herein and their pharmaceuticallyacceptable acid addition salts.

Examples of bases include, but are not limited to, alkali metal (e.g.,sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesiumand calcium) hydroxides, ammonia, and compounds of formula NW₄ ⁺,wherein W is C₁₋₄ alkyl, and the like.

Examples of salts include, but are not limited, to acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate,pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.Other examples of salts include anions of the compounds of the presentinvention compounded with a suitable cation such as Na⁺, K⁺, Ca²⁺, NH₄⁺, and NW₄ ⁺ (where W can be a C₁₋₄ alkyl group), and the like.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

As used herein, “pharmaceutical composition” or “pharmaceuticalformulation” refers to the combination of an active agent with acarrier, inert or active, making the composition especially suitable fordiagnostic or therapeutic use in vivo or ex vivo.

The phrases “pharmaceutically acceptable” and “pharmacologicallyacceptable,” as used herein, refer to compounds, molecular entities,compositions, materials, and/or dosage forms that do not produce anadverse, allergic or other untoward reaction when administered to ananimal, or a human, as appropriate. For human administration,preparations should meet sterility, pyrogenicity, and general safety andpurity standards as required by FDA Office of Biologics standards.“Pharmaceutically acceptable” and “pharmacologically acceptable” canmean approved or approvable by a regulatory agency of the federal or astate government or the corresponding agency in countries other than theUnited States, or that is listed in the U.S. Pharmacopoeia or othergenerally recognized pharmacopoeia for use in animals, and moreparticularly, in humans.

As used herein, “carrier” refers to a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent such as bempedoic acid, or a pharmaceuticallyacceptable salt thereof, from one organ, or portion of the body, toanother organ, or portion of the body.

As used herein, “pharmaceutically acceptable excipient” refers to asubstance that aids the administration of an active agent to and/orabsorption by a subject and can be included in the compositions of thepresent invention without causing a significant adverse toxicologicaleffect on the patient. Non-limiting examples of pharmaceuticallyacceptable excipients include water, NaCl, normal saline solutions, suchas a phosphate buffered saline solution, emulsions (e.g., such as anoil/water or water/oil emulsions), lactated Ringer's, normal sucrose,normal glucose, binders, fillers, disintegrants, lubricants, coatings,sweeteners, flavors, salt solutions (such as Ringer's solution),alcohols, oils, gelatins, carbohydrates such as lactose, amylose orstarch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine,and colors, and the like. Such preparations can be sterilized and, ifdesired, mixed with auxiliary agents such as lubricants, preservatives,stabilizers, wetting agents, emulsifiers, salts for influencing osmoticpressure, buffers, coloring, and/or aromatic substances and the likethat do not deleteriously react with the compounds of the invention. Forexamples of excipients, see Martin, Remington's Pharmaceutical Sciences,15th Ed., Mack Publ. Co., Easton, Pa. (1975).

As used herein, “treating” or “treatment” includes any effect, forexample, lessening, reducing, modulating, ameliorating or eliminating,that results in the improvement of the condition, disease, disorder, andthe like, or ameliorating a symptom thereof. Treating can be curing,improving, or at least partially ameliorating the disorder. In certainembodiments, treating is curing the disease.

As used herein, “reducing” or “reduction” of a symptom or symptoms (andgrammatical equivalents of this phrase) means decreasing of the severityor frequency of the symptom(s), or elimination of the symptom(s).

As used herein, “effective amount” or “therapeutically-effective amount”refers to the amount of a compound (e.g., a compound of the presentinvention) sufficient to effect beneficial or desired results. Aneffective amount can be administered in one or more administrations,applications or dosages and is not intended to be limited to aparticular formulation or administration route. As used herein, the term“treating” includes any effect, e.g., lessening, reducing, modulating,ameliorating or eliminating, that results in the improvement of thecondition, disease, disorder, and the like, or ameliorating a symptomthereof.

As used herein, “subject” and “patient” are used interchangeably andrefer to an organism to be treated by the methods and compositions ofthe present invention. Such organisms are preferably a mammal (e.g.,human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-humanprimate, such as a monkey, chimpanzee, baboon, and rhesus), and morepreferably, a human.

As used herein, “disease,” “disorder,” “condition,” or “illness,” can beused interchangeably unless otherwise underacted or understood from thecontext, refers to a state of being or health status of a patient orsubject capable of being treated with a compound, pharmaceuticalmaterials, pharmaceutical composition, or method provided herein. Insome embodiments, the compounds and methods described herein comprisereduction or elimination of one or more symptoms of the disease,disorder, or condition, or illness e.g., through administration of thecompound of formula (V), or a pharmaceutically acceptable salt thereof.

As used herein, “administering” means oral administration,administration as a suppository, topical contact, intravenous,parenteral, intraperitoneal, intramuscular, intralesional, intrathecal,intracranial, intranasal or subcutaneous administration, or theimplantation of a slow-release device, e.g., a mini-osmotic pump, to asubject. Administration is by any route, including parenteral andtransmucosal (e.g., buccal, sublingual, palatal, gingival, nasal,vaginal, rectal, or transdermal). Parenteral administration includes,e.g., intravenous, intramuscular, intra-arterial, intradermal,subcutaneous, intraperitoneal, intraventricular, and intracranial. Othermodes of delivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches, etc. By“co-administer” it is meant that a composition described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies (e.g., anti-canceragent, chemotherapeutic, or treatment for a neurodegenerative disease).The compound of the invention can be administered alone or can beco-administered to the patient. Co-administration is meant to includesimultaneous or sequential administration of the compound individuallyor in combination (more than one compound or agent). Thus, thepreparations can also be combined, when desired, with other activesubstances (e.g., to reduce metabolic degradation).

As used herein, “liver disorder” refers generally to a disease, adisorder, and/or a condition affecting the liver, and may have a widerange of severity encompassing, for example, simple accumulation of fatin the hepatocytes (steatosis), macrovescicular steatosis, periportaland lobular inflammation (steatohepatitis), cirrhosis, fibrosis, livercancers, and liver failure.

As used herein, “fatty liver disease” (“FLD”), which is also called“fatty liver,” refers to a disease leading to liver injury caused byabnormal fat accumulation in liver cells. FLD may arise from a number ofsources, including excessive alcohol consumption and metabolicdisorders, such as those associated with insulin resistance, obesity,and hypertension.

As used herein, “non-alcoholic fatty liver disease” (“NAFLD”) refers tothe spectrum of disorders resulting from an accumulation of fat in livercells in individuals with no history of excessive alcohol consumption.In the mildest form, NAFLD refers to hepatic steatosis.

As used herein, “drug-induced liver disease” or “toxic liver injury”refers to a disease or a condition in which an active agent has causedinjury to the liver.

As used herein, “alcoholic liver disease,” also called “alcoholic liverinjury,” refers to a disease caused by fat accumulation in liver cells,caused at least in part by alcohol ingestion. Examples include, but arenot limited to, diseases such as alcoholic simple fatty liver, alcoholicsteatohepatitis (“ASH”), alcoholic hepatic fibrosis, alcoholiccirrhosis, alcoholic fatty liver disease, and the like. It should benoted that alcoholic steatohepatitis is also called alcoholic fattyhepatitis and includes alcoholic hepatic fibrosis.

As used herein, “fatty liver of pregnancy” refers to acute fatty liverconditions that can arise during pregnancy and can be life-threatening.

As used herein, “altering lipid metabolism” refers to an observable(measurable) change in at least one aspect of lipid metabolism,including but not limited to total blood lipid content, blood HDLcholesterol, blood LDL cholesterol, blood VLDL cholesterol, bloodtriglyceride, blood Lp(a), blood apo A-I, blood apo E and bloodnon-esterified fatty acids.

As used herein, “altering glucose metabolism” refers to an observable(measurable) change in at least one aspect of glucose metabolism,including but not limited to total blood glucose content, blood insulin,the blood insulin to blood glucose ratio, insulin sensitivity, andoxygen consumption.

As used herein, “purified bempedoic acid” means that, when isolated as asolid, a pharmaceutical material contains at least 95% by weight of8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid based on the totalweight of the pharmaceutical material. In certain embodiments, purifiedbempedoic acid means that, when isolated as a solid, a pharmaceuticalmaterial contains at least 99.0% by weight of8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid based on the totalweight of the pharmaceutical material. In addition, purified bempedoicacid can include a pharmaceutically acceptable salt thereof, unlessstated otherwise or understood from the context.

As used herein, a reaction that is “substantially complete” means thatthe reaction contains more than about 80% by weight of the desiredproduct. In certain embodiments, a substantially complete reactioncontains more than about 90% by weight of the desired product. Incertain embodiments, a substantially complete reaction contains morethan about 95% by weight of the desired product. In certain embodiments,a substantially complete reaction contains more than about 97% by weightof the desired product.

Unless stated otherwise, all X-ray powder diffraction (XRPD) patternsdescribed herein correspond to XRPD patterns measured using a Cu Kαradiation source, and the crystalline forms of bempedoic acid areanalyzed by XRPD at ambient temperature.

II. Crystalline Forms of Bempedoic Acid A. Crystalline Bempedoic Acid

In one aspect, the invention provides a crystalline form of8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid, which is alsoknown as and referred to herein as “bempedoic acid” and/or a compound offormula (V):

In certain embodiments, the crystalline form of the compound of formula(V) may be characterized by an X-ray powder diffraction patterncomprising peaks at the following diffraction angles (2θ): 10.3±0.2,10.4±0.2, 17.9±0.2, 18.8±0.2, 19.5±0.2, and 20.7±0.2. In certainembodiments, the crystalline form of the compound of formula (V) may becharacterized by an X-ray powder diffraction pattern comprising peaks atthe following diffraction angles (2θ): 10.3±0.2, 10.4±0.2, 17.6±0.2,17.9±0.2, 18.8±0.2, 19.5±0.2, 19.7±0.2, 20.4±0.2, 20.7±0.2 and 22.6±0.2.

In certain embodiments, the crystalline form of the compound of formula(V) is characterized by the X-ray powder diffraction pattern expressedin terms of diffraction angle 2θ, and optionally inter-planar distancesd, and relative intensity (expressed as a percentage with respect to themost intense peak) as set forth in Table 1.

TABLE 1 X-ray Powder Diffraction Data of the Crystalline Form of theCompound of Formula (V) Angle [2θ] d-spacing [Å] Relative Intensity [%]5.2 16.84 2.33 10.3 8.61 70.75 10.4 8.48 78.65 11.8 7.51 2.88 13.7 6.442.72 15.5 5.73 8.08 15.6 5.67 7.16 17.3 5.12 8.20 17.6 5.04 18.72 17.94.95 100.00 18.8 4.73 42.30 19.5 4.55 21.42 19.7 4.51 15.07 20.4 4.3516.93 20.7 4.29 23.95 21.1 4.21 5.78 22.0 4.05 13.87 22.6 3.94 17.5423.1 3.84 7.78 23.6 3.78 4.97 23.9 3.73 6.19 24.7 3.60 1.98 25.8 3.463.04 26.3 3.39 2.10 27.5 3.24 13.36 29.2 3.06 3.86 30.2 2.96 1.27 30.82.90 5.34 31.3 2.86 1.40 31.9 2.81 2.95 32.9 2.72 1.27 34.4 2.61 5.9835.1 2.56 2.07 36.2 2.48 3.16 37.2 2.42 2.37 37.9 2.37 1.79

In certain embodiments, the crystalline form of the compound of formula(V) is characterized by an X-ray powder diffraction patternsubstantially the same as shown in FIG. 4.

In certain embodiments, the crystalline form of the compound of formula(V) exists in a monoclinic crystal system and has a P2₁/c space group.In certain embodiments, the crystalline form of the compound of formula(V) is characterized by the crystallographic unit cell parameters as setforth in Table 2.

TABLE 2 Unit Cell Parameters of the Crystalline Form of Compound ofFormula (V) Unit cell a = 17.9209(8) Å α = 90° dimensions b = 9.8547(5)Å β = 106.834(10)° c = 12.2775(6) γ = 90° Volume 2075.35(17) Å³ Z 4Density 1.102 Mg/m³ (calculated)

The crystalline form of the compound of formula (V) may also becharacterized according to the temperature of melting point onset.Accordingly, in certain embodiments, the crystalline form of thecompound of formula (V) has a melting point onset as determined bydifferential scanning calorimetry in the range of from about 82° C. toabout 94° C. In certain embodiments, the crystalline form of thecompound of formula (V) has a melting point onset as determined bydifferential scanning calorimetry in the range of about 90° C. to about94° C. In certain embodiments, the crystalline form of the compound offormula (V) has a melting point onset as determined by differentialscanning calorimetry at about 92° C. In certain embodiments, thecrystalline form of the compound of formula (V) has a differentialscanning calorimetry curve substantially the same as shown in FIG. 5.

The crystalline form of the compound of formula (V) may also becharacterized according to its mass gain/mass loss as a function oftemperature. Accordingly, in certain embodiments, the crystalline formof the compound of formula (V) exhibits a reduction in mass, asdetermined by thermogravimetric analysis, of from about 0.1% to about0.7% upon heating to about 200° C. In certain embodiments, thecrystalline form of the compound of formula (V) exhibits a reduction inmass, as determined by thermogravimetric analysis, of less than or equalto about 0.7% upon heating to about 200° C. In certain embodiments, thecrystalline form of the compound of formula (V) has a thermogravimetricanalysis curve substantially the same as shown in FIG. 5.

The crystalline form of the compound of formula (V) may also becharacterized according to its water sorption properties. Accordingly,in certain embodiments, the crystalline form of the compound of formula(V) exhibits a change in mass, as determined by dynamic vapor sorption,of from about 0.01% to about 0.05% at a relative humidity of 80% and atemperature of 25° C. In certain embodiments, the crystalline form ofthe compound of formula (V) exhibits a change in mass, as determined bydynamic vapor sorption, of about 0.03% at a relative humidity of 80% anda temperature of 25° C. In certain embodiments, the crystalline form ofthe compound of formula (V) has a water sorption isotherm, when measuredat 25° C., substantially the same as shown in FIG. 6.

It should be understood that reference herein to bempedoic acid or apurified bempedoic acid includes the crystalline form of bempedoic acid,unless otherwise stated or understood from the context.

B. Crystalline Salt Forms of Bempedoic Acid

In addition, it has been discovered that various crystalline salt formsof bempedoic acid can be prepared. In particular, the following counterions produced crystalline salt forms of bempedoic acid: ammonium,sodium, potassium, calcium (two crystal forms), lysine, diethylamine,ethylenediamine, piperazine, betaine, tromethamine, and isonicotinamide.

(i) Crystalline Betaine Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is acrystalline betaine salt of bempedoic acid. In certain embodiments, thecrystalline betaine salt of bempedoic acid may be characterized by anX-ray powder diffraction pattern comprising peaks at the followingdiffraction angles (2θ): 6.2±0.2, 13.5±0.2, 17.5±0.2, 19.3±0.2, and25.6±0.2. In certain embodiments, the crystalline betaine salt ofbempedoic acid may be characterized by an X-ray powder diffractionpattern comprising peaks at the following diffraction angles (2θ):6.2±0.2, 13.5±0.2, 16.1±0.2, 17.5±0.2, 19.3±0.2, 19.9±0.2, 25.6±0.2, and27.2±0.2.

In certain embodiments, the crystalline betaine salt of bempedoic acidis characterized by the X-ray powder diffraction pattern expressed interms of diffraction angle 2θ, and optionally inter-planar distances d,and relative intensity (expressed as a percentage with respect to themost intense peak) as set forth in Table 3.

TABLE 3 X-ray Powder Diffraction Data of the Crystalline Betaine Salt ofBempedoic Acid Angle [2θ] d-spacing [Å] Relative Intensity [%] 6.2014.25 95.15 10.33 8.56 1.75 11.68 7.58 6.08 12.38 7.15 3.16 13.52 6.5535.24 15.25 5.81 4.53 16.10 5.51 10.15 17.48 5.07 20.77 19.33 4.59 20.5619.94 4.45 14.49 21.48 4.14 5.58 25.64 3.47 29.74 27.24 3.27 13.51 31.472.84 7.33 39.02 2.31 2.27

(ii) Crystalline Calcium Salt Forms of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is acrystalline calcium salt of bempedoic acid. In certain embodiments, thecrystalline calcium salt of bempedoic acid may be characterized by anX-ray powder diffraction pattern comprising peaks at the followingdiffraction angles (2θ): 4.9±0.2, 9.1±0.2, and 19.7±0.2. In certainembodiments, the crystalline calcium salt of bempedoic acid may becharacterized by an X-ray powder diffraction pattern comprising peaks atthe following diffraction angles (2θ): 4.9±0.2, 6.4±0.2, 9.1±0.2,14.8±0.2, 19.7±0.2, and 37.1±0.2.

In certain embodiments, the crystalline calcium salt of bempedoic acidis characterized by the X-ray powder diffraction pattern expressed interms of diffraction angle 2θ, and optionally inter-planar distances d,and relative intensity (expressed as a percentage with respect to themost intense peak) as set forth in Table 4.

TABLE 4 X-ray Powder Diffraction Data of the Crystalline Calcium Salt ofBempedoic Acid Angle [2θ] d-spacing [Å] Relative Intensity [%] 4.8618.16 21.41 6.44 13.72 5.99 7.51 11.77 1.16 9.15 9.67 59.65 12.25 7.221.94 14.79 5.99 6.51 16.11 5.50 4.16 19.71 4.50 10.32 27.26 3.27 2.0732.66 2.74 1.12 37.10 2.42 5.22 38.55 2.34 1.40

In certain embodiments, the crystalline calcium salt of bempedoic acidmay be characterized by an X-ray powder diffraction pattern comprisingpeaks at the following diffraction angles (2θ): 6.0±0.2, 6.8±0.2,8.5±0.2, and 9.8±0.2. In certain embodiments, the crystalline calciumsalt of bempedoic acid may be characterized by an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 6.0±0.2, 6.8±0.2, 8.5±0.2, 9.8±0.2, 17.1±0.2, and 19.0±0.2.

In certain embodiments, the crystalline calcium salt of bempedoic acidis characterized by the X-ray powder diffraction pattern expressed interms of diffraction angle 2θ, and optionally inter-planar distances d,and relative intensity (expressed as a percentage with respect to themost intense peak) as set forth in Table 5.

TABLE 5 X-ray Powder Diffraction Data of the Crystalline Calcium Salt ofBempedoic Acid Angle [2θ] d-spacing [Å] Relative Intensity [%] 6.0314.65 49.46 6.79 13.01 28.89 8.53 10.37 100.00 9.80 9.02 77.92 12.057.35 2.31 14.09 6.29 4.03 17.10 5.18 13.68 19.03 4.66 5.37 33.15 2.700.90 35.89 2.50 1.92

(iii) Crystalline Diethylamine Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is acrystalline diethylamine salt of bempedoic acid. In certain embodiments,the crystalline diethylamine salt of bempedoic acid may be characterizedby an X-ray powder diffraction pattern comprising peaks at the followingdiffraction angles (2θ): 9.6±0.2, 14.1±0.2, and 19.8±0.2. In certainembodiments, the crystalline diethylamine salt of bempedoic acid may becharacterized by an X-ray powder diffraction pattern comprising peaks atthe following diffraction angles (2θ): 9.6±0.2, 14.1±0.2, 17.8±0.2,19.8±0.2, 22.6±0.2, and 38.7±0.2.

In certain embodiments, the crystalline diethylamine salt of bempedoicacid is characterized by the X-ray powder diffraction pattern expressedin terms of diffraction angle 2θ, and optionally inter-planar distancesd, and relative intensity (expressed as a percentage with respect to themost intense peak) as set forth in Table 6.

TABLE 6 X-ray Powder Diffraction Data of the Crystalline DiethylamineSalt of Bempedoic Acid Angle [2θ] d-spacing [Å] Relative Intensity [%]9.55 9.26 29.82 14.08 6.29 69.49 17.79 4.99 11.34 19.77 4.49 37.13 22.603.93 3.08 38.70 2.33 6.24

(iv) Crystalline Ethylenediamine Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is acrystalline ethylenediamine salt of bempedoic acid. In certainembodiments, the crystalline ethylenediamine salt of bempedoic acid maybe characterized by an X-ray powder diffraction pattern comprising peaksat the following diffraction angles (2θ): 6.8±0.2, 10.8±0.2, 16.2±0.2,18.3±0.2, and 18.8±0.2. In certain embodiments, the crystallineethylenediamine salt of bempedoic acid may be characterized by an X-raypowder diffraction pattern comprising peaks at the following diffractionangles (2θ): 6.8±0.2, 7.7±0.2, 10.8±0.2, 13.9±0.2, 15.2±0.2, 16.2±0.2,18.3±0.2, 18.8±0.2, 21.4±0.2, and 22.3±0.2.

In certain embodiments, the crystalline ethylenediamine salt ofbempedoic acid is characterized by the X-ray powder diffraction patternexpressed in terms of diffraction angle 2θ, and optionally inter-planardistances d, and relative intensity (expressed as a percentage withrespect to the most intense peak) as set forth in Table 7.

TABLE 7 X-ray Powder Diffraction Data of the Crystalline EthylenediamineSalt of Bempedoic Acid Angle [2θ] d-spacing [Å] Relative Intensity [%]6.76 13.07 66.63 7.73 11.44 52.39 10.83 8.17 85.3 13.53 6.54 19.73 13.926.36 24.35 15.23 5.82 29.21 16.23 5.46 100.00 16.71 5.31 10.30 17.395.10 10.74 18.28 4.85 71.04 18.84 4.71 53.54 19.74 4.50 11.79 20.96 4.2412.84 21.37 4.16 24.85 21.65 4.10 22.22 22.25 4.00 28.05 22.85 3.8921.63 24.86 3.58 17.81 26.03 3.42 3.96 27.02 3.30 7.08 28.10 3.18 10.2428.33 3.15 12.26 31.17 2.87 9.27 32.07 2.79 8.88 33.13 2.70 6.27 34.602.59 3.21 37.45 2.40 3.41

(v) Crystalline Isonicotinamide Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is acrystalline isonicotinamide salt of bempedoic acid. In certainembodiments, the crystalline isonicotinamide salt of bempedoic acid maybe characterized by an X-ray powder diffraction pattern comprising peaksat the following diffraction angles (2θ): 4.4±0.2, 18.8±0.2, 20.1±0.2,and 24.5±0.2. In certain embodiments, the crystalline isonicotinamidesalt of bempedoic acid may be characterized by an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 4.4±0.2, 14.5±0.2, 18.8±0.2, 20.1±0.2, 24.5±0.2, 26.2±0.2, and29.5±0.2.

In certain embodiments, the crystalline isonicotinamide salt ofbempedoic acid is characterized by the X-ray powder diffraction patternexpressed in terms of diffraction angle 2θ, and optionally inter-planardistances d, and relative intensity (expressed as a percentage withrespect to the most intense peak) as set forth in Table 8.

TABLE 8 X-ray Powder Diffraction Data of the Crystalline IsonicotinamideSalt of Bempedoic Acid Angle [2θ] d-spacing [Å] Relative Intensity [%]4.36 20.26 31.75 8.89 9.95 0.44 11.49 7.70 1.86 13.05 6.78 1.75 14.476.12 4.77 18.36 4.83 3.21 18.84 4.71 15.30 20.09 4.42 13.54 24.51 3.638.22 25.90 3.44 2.54 26.24 3.40 4.32 26.76 3.33 2.22 27.69 3.22 1.4428.69 3.11 1.38 29.49 3.03 3.67 30.08 2.97 1.49 30.77 2.91 1.16 32.562.75 1.14 34.83 2.58 1.16 36.79 2.44 0.69

(vi) Crystalline Potassium Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is acrystalline potassium salt of bempedoic acid. In certain embodiments,the crystalline potassium salt of bempedoic acid may be characterized byan X-ray powder diffraction pattern comprising peaks at the followingdiffraction angles (2θ): 5.7±0.2, 7.3±0.2, 9.6±0.2, and 22.1±0.2. Incertain embodiments, the crystalline potassium salt of bempedoic acidmay be characterized by an X-ray powder diffraction pattern comprisingpeaks at the following diffraction angles (2θ): 5.7±0.2, 7.3±0.2,9.6±0.2, 16.0±0.2, 22.1±0.2, and 23.0±0.2.

In certain embodiments, the crystalline potassium salt of bempedoic acidis characterized by the X-ray powder diffraction pattern expressed interms of diffraction angle 2θ, and optionally inter-planar distances d,and relative intensity (expressed as a percentage with respect to themost intense peak) as set forth in Table 9.

TABLE 9 X-ray Powder Diffraction Data of the Crystalline Potassium Saltof Bempedoic Acid Angle [2θ] d-spacing [Å] Relative Intensity [%] 5.7115.48 95.20 7.33 12.06 100.00 9.58 9.23 17.10 15.99 5.54 9.16 22.10 4.0218.51 22.97 3.87 3.21 24.83 3.59 2.48 29.94 2.98 0.86 37.72 2.39 1.40

(vii) Crystalline Lysine Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is acrystalline lysine salt of bempedoic acid. In certain embodiments, thecrystalline lysine salt of bempedoic acid may be characterized by anX-ray powder diffraction pattern comprising peaks at the followingdiffraction angles (2θ): 4.2±0.2, 10.2±0.2, 19.1±0.2, 19.7±0.2, and21.9±0.2. In certain embodiments, the crystalline lysine salt ofbempedoic acid may be characterized by an X-ray powder diffractionpattern comprising peaks at the following diffraction angles (2θ):4.2±0.2, 10.2±0.2, 13.5±0.2, 14.2±0.2, 16.0±0.2, 19.1±0.2, 19.7±0.2, and21.9±0.2.

In certain embodiments, the crystalline lysine salt of bempedoic acid ischaracterized by the X-ray powder diffraction pattern expressed in termsof diffraction angle 2θ, and optionally inter-planar distances d, andrelative intensity (expressed as a percentage with respect to the mostintense peak) as set forth in Table 10.

TABLE 10 X-ray Powder Diffraction Data of the Crystalline Lysine Salt ofBempedoic Acid Angle [2θ] d-spacing [Å] Relative Intensity [%] 4.2220.95 79.22 10.23 8.65 24.52 13.53 6.55 18.67 14.22 6.23 20.50 15.965.55 16.26 19.12 4.64 100.00 19.68 4.51 30.60 21.91 4.06 36.00 23.093.85 11.64 25.45 3.50 13.58 33.18 2.70 4.36

(viii) Crystalline Sodium Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is acrystalline sodium salt of bempedoic acid. In certain embodiments, thecrystalline sodium salt of bempedoic acid may be characterized by anX-ray powder diffraction pattern comprising peaks at the followingdiffraction angles (2θ): 6.1±0.2, 14.2±0.2, 18.3±0.2, and 24.5±0.2. Incertain embodiments, the crystalline sodium salt of bempedoic acid maybe characterized by an X-ray powder diffraction pattern comprising peaksat the following diffraction angles (2θ): 6.1±0.2, 13.4±0.2, 14.2±0.2,16.6±0.2, 18.3±0.2, 19.1±0.2, and 24.5±0.2.

In certain embodiments, the crystalline sodium salt of bempedoic acid ischaracterized by the X-ray powder diffraction pattern expressed in termsof diffraction angle 2θ, and optionally inter-planar distances d, andrelative intensity (expressed as a percentage with respect to the mostintense peak) as set forth in Table 11.

TABLE 11 X-ray Powder Diffraction Data of the Crystalline Sodium Salt ofBempedoic Acid Angle [2θ] d-spacing [Å] Relative Intensity [%] 6.1014.48 100.00 8.16 10.83 1.15 10.89 8.13 2.68 12.19 7.28 3.98 13.36 6.636.65 14.22 6.23 11.60 16.63 5.33 8.50 16.86 5.26 1.01 18.32 4.84 24.1019.12 4.64 9.38 21.36 4.16 1.36 21.83 4.07 1.51 22.07 4.03 2.91 22.423.97 1.34 22.67 3.92 1.91 24.08 3.70 3.19 24.50 3.63 11.00 25.11 3.553.04 28.92 3.09 0.79 29.79 3.00 1.62 30.77 2.91 1.87 32.32 2.77 0.5933.02 2.71 1.13 34.12 2.63 0.32 37.11 2.42 0.34 37.89 2.37 0.41 38.772.32 0.40

(ix) Crystalline Ammonium Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is acrystalline ammonium salt of bempedoic acid. In certain embodiments, thecrystalline ammonium salt of bempedoic acid may be characterized by anX-ray powder diffraction pattern comprising peaks at the followingdiffraction angles (2θ): 6.9±0.2, 7.1±0.2, 14.3±0.2, 16.0±0.2, and21.4±0.2. In certain embodiments, the crystalline ammonium salt ofbempedoic acid may be characterized by an X-ray powder diffractionpattern comprising peaks at the following diffraction angles (2θ):6.9±0.2, 7.1±0.2, 9.3±0.2, 14.3±0.2, 16.0±0.2, 18.2±0.2, 19.2±0.2,21.4±0.2, and 22.3±0.2.

In certain embodiments, the crystalline ammonium salt of bempedoic acidis characterized by the X-ray powder diffraction pattern expressed interms of diffraction angle 2θ, and optionally inter-planar distances d,and relative intensity (expressed as a percentage with respect to themost intense peak) as set forth in Table 12.

TABLE 12 X-ray Powder Diffraction Data of the Crystalline Ammonium Saltof Bempedoic Acid Angle [2θ] d-spacing [Å] Relative Intensity [%] 6.9212.78 32.02 7.12 12.41 52.37 9.27 9.54 25.96 12.37 7.15 11.85 14.26 6.2145.64 15.96 5.55 47.86 16.72 5.30 22.51 17.08 5.19 24.62 18.16 4.8933.61 19.17 4.63 31.17 21.43 4.15 44.99 22.26 3.99 31.44 24.05 3.7016.43 24.56 3.62 10.08 27.32 3.26 12.47 27.79 3.21 9.98 27.98 3.19 10.0129.36 3.04 3.14 29.83 3.00 3.47 30.30 2.95 4.46 30.94 2.89 4.92 35.562.52 14.29 36.67 2.45 5.59 37.62 2.39 2.72 38.66 2.33 2.81

(x) Crystalline Piperazine Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is acrystalline piperazine salt of bempedoic acid. In certain embodiments,the crystalline piperazine salt of bempedoic acid may be characterizedby an X-ray powder diffraction pattern comprising peaks at the followingdiffraction angles (2θ): 6.7±0.2, 8.7±0.2, 10.7±0.2, 15.7±0.2, and16.0±0.2. In certain embodiments, the crystalline piperazine salt ofbempedoic acid may be characterized by an X-ray powder diffractionpattern comprising peaks at the following diffraction angles (2θ):6.7±0.2, 8.7±0.2, 10.7±0.2, 15.7±0.2, 16.0±0.2, 19.4±0.2, 20.1±0.2, and21.4±0.2.

In certain embodiments, the crystalline piperazine salt of bempedoicacid is characterized by the X-ray powder diffraction pattern expressedin terms of diffraction angle 2θ, and optionally inter-planar distancesd, and relative intensity (expressed as a percentage with respect to themost intense peak) as set forth in Table 13.

TABLE 13 X-ray Powder Diffraction Data of the Crystalline PiperazineSalt of Bempedoic Acid Angle [2θ] d-spacing [Å] Relative Intensity [%]6.66 13.27 74.02 8.69 10.18 40.75 10.70 8.27 33.84 13.35 6.63 11.7915.68 5.65 48.82 15.99 5.54 100.00 19.38 4.58 23.99 20.10 4.42 18.2321.35 4.16 18.56 27.52 3.24 3.45 28.61 3.12 6.01 34.01 2.64 5.19

(xi) Crystalline Tromethamine Salt Form of Bempedoic Acid

In certain embodiments, the crystalline salt form of bempedoic acid is acrystalline tromethamine salt of bempedoic acid. In certain embodiments,the crystalline tromethamine salt of bempedoic acid may be characterizedby an X-ray powder diffraction pattern comprising peaks at the followingdiffraction angles (2θ): 6.6±0.2, 18.2±0.2, 18.6±0.2, and 19.8±0.2. Incertain embodiments, the crystalline tromethamine salt of bempedoic acidmay be characterized by an X-ray powder diffraction pattern comprisingpeaks at the following diffraction angles (2θ): 6.6±0.2, 13.6±0.2,18.2±0.2, 18.6±0.2, 19.8±0.2, and 26.5±0.2.

In certain embodiments, the crystalline tromethamine salt of bempedoicacid is characterized by the X-ray powder diffraction pattern expressedin terms of diffraction angle 2θ, and optionally inter-planar distancesd, and relative intensity (expressed as a percentage with respect to themost intense peak) as set forth in Table 14.

TABLE 14 X-ray Powder Diffraction Data of the Crystalline TromethamineSalt of Bempedoic Acid Angle [2θ] d-spacing [Å] Relative Intensity [%]6.60 13.39 100.00 9.10 9.72 1.10 13.57 6.53 1.90 13.94 6.35 1.47 17.085.19 1.34 18.19 4.88 2.33 18.62 4.77 2.76 19.31 4.60 1.40 19.79 4.4910.06 21.68 4.10 0.33 26.55 3.36 2.17 28.21 3.16 0.61 30.67 2.92 0.2733.69 2.66 0.24

C. Co-Crystal Forms of Bempedoic Acid

Moreover, it was discovered that certain co-crystal forms of bempedoicacid could be prepared. In particular, the following co-formers producedco-crystals with bempedoic acid:palmitic acid and aspartame (two crystalforms).

(i) Co-Crystal of Bempedoic Acid and Aspartame

In certain embodiments, the co-crystal form of bempedoic acid is aco-crystal form of bempedoic acid and aspartame. In certain embodiments,the co-crystal form of bempedoic acid and aspartame may be characterizedby an X-ray powder diffraction pattern comprising peaks at the followingdiffraction angles (2θ): 7.6±0.2, 8.6±0.2, 17.3±0.2, 18.4±0.2, and25.1±0.2. In certain embodiments, the co-crystal form of bempedoic acidand aspartame may be characterized by an X-ray powder diffractionpattern comprising peaks at the following diffraction angles (2θ):7.6±0.2, 8.6±0.2, 14.4±0.2, 17.3±0.2, 18.4±0.2, 25.1±0.2, 25.2±0.2,26.1.

In certain embodiments, the co-crystal form of bempedoic acid andaspartame is characterized by the X-ray powder diffraction patternexpressed in terms of diffraction angle 2θ, and optionally inter-planardistances d, and relative intensity (expressed as a percentage withrespect to the most intense peak) as set forth in Table 15.

TABLE 15 X-ray Powder Diffraction Data of the Co-crystal Form ofBempedoic Acid and Aspartame Angle [2θ] d-spacing [Å] Relative Intensity[%] 7.6 11.60 82.14 8.6 10.23 22.88 13.3 6.67 3.69 14.4 6.14 19.99 15.35.80 7.52 17.3 5.12 32.09 18.4 4.82 100.00 20.9 4.26 4.07 23.0 3.87 6.9825.1 3.54 23.14 25.2 3.53 17.65 26.1 3.42 19.40 29.0 3.08 1.60 31.2 2.878.23 32.4 2.76 2.29 35.6 2.52 2.32 36.6 2.45 3.48

In certain embodiments, the co-crystal form of bempedoic acid andaspartame may be characterized by an X-ray powder diffraction patterncomprising peaks at the following diffraction angles (2θ): 4.4±0.2,6.8±0.2, 10.6±0.2, 13.2±0.2, and 18.4±0.2. In certain embodiments, theco-crystal form of bempedoic acid and aspartame may be characterized byan X-ray powder diffraction pattern comprising peaks at the followingdiffraction angles (2θ): 4.4±0.2, 5.6±0.2, 6.8±0.2, 10.6±0.2, 12.3±0.2,13.2±0.2, 13.6±0.2, 16.2±0.2, 17.6±0.2, and 18.4±0.2.

In certain embodiments, the co-crystal form of bempedoic acid andaspartame is characterized by the X-ray powder diffraction patternexpressed in terms of diffraction angle 2θ, and optionally inter-planardistances d, and relative intensity (expressed as a percentage withrespect to the most intense peak) as set forth in Table 16.

TABLE 16 X-ray Powder Diffraction Data of the Co-crystal Form ofBempedoic Acid and Aspartame Angle [2θ] d-spacing [Å] Relative Intensity[%] 4.4 20.07 100.00 5.6 15.71 18.95 6.8 13.01 23.46 8.6 10.27 3.51 10.68.38 26.31 12.3 7.22 14.92 13.2 6.70 23.91 13.6 6.53 18.83 16.2 5.4715.84 16.8 5.28 13.01 17.6 5.03 19.15 18.4 4.83 25.66 19.0 4.68 12.7622.9 3.88 8.04 25.1 3.54 5.95 29.2 3.05 6.26 31.0 2.89 5.42 31.5 2.835.95 32.9 2.72 4.77

(ii) Co-Crystal of Bempedoic Acid and Palmitic Acid

In certain embodiments, the co-crystal form of bempedoic acid is aco-crystal form of bempedoic acid and palmitic acid. In certainembodiments, the co-crystal form of bempedoic acid and palmitic acid maybe characterized by an X-ray powder diffraction pattern comprising peaksat the following diffraction angles (2θ): 4.3±0.2, 6.3±0.2, 8.5±0.2, and17.0±0.2. In certain embodiments, the co-crystal form of bempedoic acidand palmitic acid may be characterized by an X-ray powder diffractionpattern comprising peaks at the following diffraction angles (2θ):4.3±0.2, 6.3±0.2, 8.5±0.2, 10.5±0.2, 17.0±0.2, and 25.5±0.2.

In certain embodiments, the co-crystal form of bempedoic acid andpalmitic acid is characterized by the X-ray powder diffraction patternexpressed in terms of diffraction angle 2θ, and optionally inter-planardistances d, and relative intensity (expressed as a percentage withrespect to the most intense peak) as set forth in Table 17.

TABLE 17 X-ray Powder Diffraction Data of the Co-crystal Form ofBempedoic Acid and Palmitic Acid Angle [2θ] d-spacing [Å] RelativeIntensity [%] 4.3 20.74 100.00 6.3 14.00 27.40 8.5 10.42 11.40 10.5 8.416.34 17.0 5.22 9.46 21.2 4.19 4.72 24.6 3.61 4.33 25.5 3.49 4.99 29.92.99 2.02 34.4 2.61 2.54

III. Methods of Preparing Bempedoic Acid Including Purified BempedoicAcid

As described herein, in one aspect, the invention provides methods ofpreparing 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid, which isa compound of formula (V):

which methods also include making a pharmaceutically acceptable saltthereof.

It should be understood that methods of the invention include preparingbempedoic acid. In certain embodiments, the methods of preparingbempedoic acid result in purified bempedoic acid, which also can bedescribed herein with respect to a pharmaceutical material, i.e., apharmaceutical material comprising an amount of bempedoic acid or anamount of a compound of formula (V), or a pharmaceutically acceptablesalt thereof. These terms and phrases can be used interchangeablyherein, unless otherwise stated or understood from the context.

Accordingly, in various embodiments, methods are provided for preparinga pharmaceutical material comprising a compound of formula (V):

or a pharmaceutically acceptable salt thereof.

In various embodiments, the methods generally include:

(a) contacting ethyl isobutyrate with a substituted 5-chloropentane inthe presence of a first base to form a compound of formula (I):

wherein the substituted 5-chloropentane is selected from the groupconsisting of 1-bromo-5-chloropentane and 1-iodo-5-chloropentane;

(b) contacting the compound of formula (I) with a salt of formula[M]⁺[X]⁻ to form a compound of formula (II):

wherein [M]⁺ is selected from the group consisting of Li⁺, Na⁺ and K⁺,wherein [X]⁻ is selected from the group consisting of Br⁻ and I⁻;

(c) contacting the compound of formula (II) with toluenesulfonylmethylisocyanide in the presence of a second base to form a firstintermediate, and contacting the first intermediate with an acid to forma compound of formula (IV):

and

(d) contacting the compound of formula (IV) with a reducing agent toform a second intermediate, and contacting the second intermediate witha hydrolyzing base to form a compound of formula (V).

In certain embodiments of the invention, the method further comprises:

(e) purifying the compound of formula (V) to provide a pharmaceuticalmaterial comprising a purified amount of the compound of formula (V).

Synthesis of a Compound of Formula (I)—Step (a)

In various embodiments, synthesis of the compound of formula (I):

generally comprises contacting ethyl isobutyrate with a substituted5-chloropentane in the presence of a first base.

In certain embodiments, in step (a), contacting ethyl isobutyrate withthe substituted 5-chloropentane in the presence of a first base isconducted at a temperature in the range of from about −30° C. to about10° C., from about −25° C. to about 10° C., from about −20° C. to about10° C., from about −18° C. to about 10° C., from about −15° C. to about10° C., from about −10° C. to about 10° C., from about −5° C. to about10° C., from about 0° C. to about 10° C., from about 5° C. to about 10°C., from about −30° C. to about 5° C., from about −30° C. to about 0°C., from about −30° C. to about −5° C., from about −30° C. to about −10°C., from about −30° C. to about −15° C., from about −30° C. to about−18° C., from about −30° C. to about −20° C., from about −30° C. toabout −25° C., from about −25° C. to about 5° C., from about −25° C. toabout 0° C., from about −25° C. to about −5° C., from about −25° C. toabout −10° C., from about −25° C. to about −15° C., from about −25° C.to about −18° C., from about −25° C. to about −20° C., from about −20°C. to about 5° C., from about −20° C. to about 0° C., from about −20° C.to about −5° C., from about −20° C. to about −10° C., from about −20° C.to about −15° C., from about −20° C. to about −18° C., from about −18°C. to about 5° C., from about −18° C. to about 0° C., from about −18° C.to about −5° C., from about −18° C. to about −10° C., from about −18° C.to about −15° C., from about −15° C. to about 5° C., from about −15° C.to about 0° C., from about −15° C. to about −5° C., from about −15° C.to about −10° C., from about −10° C. to about 5° C., from about −10° C.to about 0° C., from about −10° C. to about −5° C., from about −5° C. toabout 5° C., or from about −5° C. to about 0° C. In certain embodiments,in step (a), contacting ethyl isobutyrate with the substituted5-chloropentane in the presence of a first base is conducted at atemperature in the range of from about −20° C. to about 0° C. In certainembodiments, in step (a), contacting ethyl isobutyrate with thesubstituted 5-chloropentane in the presence of a first base is conductedat a temperature in the range of from about −18° C. to about −5° C.

In certain embodiments, in step (a), less than about 0.5% by weight,about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about0.9% by weight, about 1% by weight, about 1.1% by weight, about 1.2% byweight, about 1.3% by weight, about 1.4% by weight, or about 1.5% byweight of the substituted 5-chloropentane remains after forming thecompound of formula (I). In some embodiments, in step (a), less thanabout 1% by weight of the substituted 5-chloropentane remains afterforming the compound of formula (I).

In certain embodiments, in step (a), the molar ratio of ethylisobutyrate to the substituted 5-chloropentane is about 1:1, about1.01:1, about 1.02:1, about 1.03:1, about 1.04:1, about 1.05:1, about1.06:1, about 1.07:1, about 1.08:1, about 1.09:1, about 1.1:1, about1.11:1, about 1.12:1, about 1.13:1, about 1.14:1, about 1.15:1, about1.16:1, about 1.17:1, about 1.18:1, about 1.19:1, about 1.2:1, or about1.21:1, including the ranges between each of these ratios. In someembodiments, in step (a), the molar ratio of ethyl isobutyrate to thesubstituted 5-chloropentane is about 1.1:1. In some embodiments, themolar ratio of ethyl isobutyrate to the substituted 5-chloropentane isfrom about 1.1:1 to about 1.21:1.

In certain embodiments, in step (a), the substituted 5-chloropentane iscontacted ethyl isobutyrate, which is present in an amount of about 1molar equivalent, about 1.01 molar equivalents, about 1.02 molarequivalents, about 1.03 molar equivalents, about 1.04 molar equivalents,about 1.05 molar equivalents, about 1.06 molar equivalents, about 1.07molar equivalents, about 1.08 molar equivalents, about 1.09 molarequivalents, about 1.1 molar equivalents, about 1.11 molar equivalents,about 1.12 molar equivalents, about 1.13 molar equivalents, about 1.14molar equivalents, about 1.15 molar equivalents, about 1.16 molarequivalents, about 1.17 molar equivalents, about 1.18 molar equivalents,about 1.19 molar equivalents, about 1.2 molar equivalents, or about 1.21molar equivalents. In some embodiments, in step (a), the substituted5-chloropentane is contacted with about 1.1 molar equivalents of ethylisobutyrate.

In certain embodiments, in step (a), contacting ethyl isobutyrate andthe substituted 5-chloropentane occurs by adding ethyl isobutyrate andthe substituted 5-chloropentane to a reactor. In some embodiments, instep (a), adding ethyl isobutyrate and the substituted 5-chloropentaneto the reactor occurs at a temperature of less than about 10° C., lessthan about 5° C., less than about 0° C., less than about −5° C., lessthan about −10° C., less than about −15° C., less than about −20° C.,less than about −25° C., or less than about −30° C. In some embodiments,in step (a), adding ethyl isobutyrate and the substituted5-chloropentane to the reactor occurs at a temperature of about 10° C.,about 5° C., about 0° C., about −5° C., about −7° C., about −10° C.,about −12° C., about −14° C., about −16° C., about −18° C., about −20°C., about −22° C., about −24° C., about −26° C., about −28° C., or about−30° C. In some embodiments, in step (a), adding ethyl isobutyrate andthe substituted 5-chloropentane to the reactor occurs at a temperatureof about −5° C. In some embodiments, in step (a), adding ethylisobutyrate and the substituted 5-chloropentane to the reactor occurs ata temperature of about −12° C. In some embodiments, in step (a), addingethyl isobutyrate and the substituted 5-chloropentane to the reactoroccurs at a temperature of about −18° C.

In certain embodiments, in step (a), the time of adding ethylisobutyrate and the substituted 5-chloropentane to the reactor is about5 mins, about 10 mins, about 15 mins, about 20 mins, about 30 mins,about 40 mins, about 50 mins, about 1 hour, about 2 hours, about 3hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12hours.

In certain embodiments, in step (a), the time of adding ethylisobutyrate and the substituted 5-chloropentane to the reactor is fromabout 10 mins to about 60 mins, from about 20 mins to about 60 mins,from about 30 mins to about 60 mins, from about 40 mins to about 60mins, from about 50 mins to about 60 mins, from about 10 mins to about50 mins, from about 10 mins to about 40 mins, from about 10 mins toabout 30 mins, from about 10 mins to about 20 mins, from about 20 minsto about 50 mins, from about 20 mins to about 40 mins, from about 20mins to about 30 mins, from about 30 mins to about 50 mins, from about30 mins to about 40 mins, or from about 40 mins to about 50 mins.

In certain embodiments, in step (a), the time of adding ethylisobutyrate and the substituted 5-chloropentane to the reactor is fromabout 1 hour to about 12 hours, from about 2 hours to about 12 hours,from about 3 hours to about 12 hours, from about 4 hours to about 12hours, from about 5 hours to about 12 hours, from about 6 hours to about12 hours, from about 7 hours to about 12 hours, from about 8 hours toabout 12 hours, from about 9 hours to about 12 hours, from about 10hours to about 12 hours, from about 11 hours to about 12 hours, fromabout 1 hours to about 11 hours, from about 1 hours to about 10 hours,from about 1 hours to about 9 hours, from about 1 hours to about 8hours, from about 1 hours to about 7 hours, from about 1 hours to about6 hours, from about 1 hours to about 5 hours, from about 1 hours toabout 4 hours, from about 1 hours to about 3 hours, from about 1 hoursto about 2 hours, from about 2 hours to about 11 hours, from about 2hours to about 10 hours, from about 2 hours to about 9 hours, from about2 hours to about 8 hours, from about 2 hours to about 7 hours, fromabout 2 hours to about 6 hours, from about 2 hours to about 5 hours,from about 2 hours to about 4 hours, from about 2 hours to about 3hours, from about 3 hours to about 11 hours, from about 3 hours to about10 hours, from about 3 hours to about 9 hours, from about 3 hours toabout 8 hours, from about 3 hours to about 7 hours, from about 3 hoursto about 6 hours, from about 3 hours to about 5 hours, from about 3hours to about 4 hours, from about 4 hours to about 11 hours, from about4 hours to about 10 hours, from about 4 hours to about 9 hours, fromabout 4 hours to about 8 hours, from about 4 hours to about 7 hours,from about 4 hours to about 6 hours, from about 4 hours to about 5hours, from about 5 hours to about 11 hours, from about 5 hours to about10 hours, from about 5 hours to about 9 hours, from about 5 hours toabout 8 hours, from about 5 hours to about 7 hours, from about 5 hoursto about 6 hours, from about 6 hours to about 11 hours, from about 6hours to about 10 hours, from about 6 hours to about 9 hours, from about6 hours to about 8 hours, from about 6 hours to about 7 hours, fromabout 7 hours to about 11 hours, from about 7 hours to about 10 hours,from about 7 hours to about 9 hours, from about 7 hours to about 8hours, from about 8 hours to about 11 hours, from about 8 hours to about10 hours, from about 8 hours to about 9 hours, from about 9 hours toabout 11 hours, from about 9 hours to about 10 hours, or from about 10hours to about 11 hours.

In some embodiments, adding ethyl isobutyrate and the substituted5-chloropentane to the reactor occurs simultaneously. In someembodiments, adding ethyl isobutyrate to the reactor occurs prior toadding the substituted 5-chloropentane to the reactor. In someembodiments, adding ethyl isobutyrate to the reactor occurs after addingthe substituted 5-chloropentane to the reactor.

In certain embodiments, contacting ethyl isobutyrate with thesubstituted 5-chloropentane in the presence of a first base forms areaction mixture. In certain embodiments, in step (a), at the end of thereaction, the methods include quenching the reaction mixture with anacid. In some embodiments, the acid is hydrochloric acid.

In certain embodiments, ethyl isobutyrate and the substituted5-chloropentane are starting materials used in the production of thecompound of formula (I). In certain embodiments, the purity of thesubstituted 5-chloropentane is ≥99%, ≥99.1%, ≥99.2%, ≥99.3%, ≥99.4%,≥99.5%, ≥99.6%, ≥99.7%, ≥99.8%, or ≥99.9%, as measured by gaschromatography (GC). In some embodiments, the purity of the substituted5-chloropentane is ≥99%, as measured by GC.

In certain embodiments, the purity of ethyl isobutyrate is ≥99%, ≥99.1%,≥99.2%, ≥99.3%, ≥99.4%, ≥99.5%, ≥99.6%, ≥99.7%, ≥99.8%, or ≥99.9%, asmeasured by gas chromatography (GC). In some embodiments, the purity ofethyl isobutyrate is ≥99.5%, as measured by GC.

In certain embodiments, the concentration of ethanol present in ethylisobutyrate is ≤0.05%, ≤0.06%, ≤0.07%, ≤0.08%, ≤0.09%, ≤0.1%, ≤0.11%,≤0.12%, ≤0.13%, ≤0.14%, or ≤0.15%, as measured by GC. In someembodiments, the concentration of ethanol present in ethyl isobutyrateis ≤0.1%, as measured by GC.

In certain embodiments, the substituted 5-chloropentane is1-iodo-5-chloropentane. In certain embodiments, the substituted5-chloropentane is 1-bromo-5-chloropentane.

In certain embodiments, the purity of 1-iodo-5-chloropentane or1-bromo-5-chloropentane is ≥99%, ≥99.1%, ≥99.2%, ≥99.3%, ≥99.4%, ≥99.5%,≥99.6%, ≥99.7%, ≥99.8%, or ≥99.9%, as measured by gas chromatography(GC).

In certain embodiments, in step (a), the first base is selected from thegroup consisting of lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, sodium hydride, sodium amide, lithium amide,and lithium tetramethylpiperidide. In some embodiments, in step (a), thefirst base is lithium diisopropylamide.

In certain embodiments, the amount of unreacted substituted5-chloropentane remaining upon completion of step (a) is ≤0.05%, ≤0.06%,≤0.07%, ≤0.08%, ≤0.09%, ≤0.1%, ≤0.11%, ≤0.12%, ≤0.12%, ≤0.13%, ≤0.14%,≤0.15%, ≤0.16%, ≤0.17%, ≤0.18%, ≤0.19%, or ≤0.2%, as measured by GC. Insome embodiments, the amount of unreacted substituted 5-chloropentaneremaining upon completion of step (a) is ≤0.21%, ≤0.22%, ≤0.23%, ≤0.24%,≤0.25%, ≤0.25%, ≤0.26%, ≤0.27%, ≤0.28%, ≤0.29%, ≤0.3%, ≤0.31%, ≤0.32%,≤0.33%, ≤0.34%, ≤0.35%, ≤0.36%, ≤0.37%, ≤0.38%, ≤0.39%, or ≤0.4%, asmeasured by GC.

Synthesis of Lithium Diisopropylamide (A First Base for Making theCompound of Formula (I))

In various embodiments, the synthesis of lithium diisopropylamide, whichis a base used for making the compound of formula (I):

generally comprises contacting diisopropylamine with butyllithium.

In certain embodiments, the molar ratio of butyllithium todiisopropylamine is about 1:1.04, about 1:1.05, about 1:1.06, about1:1.07, about 1:1.08, about 1:1.09, about 1:1.1, about 1:1.2, about1:1.3, about 1:1.4, about 1:1.5, or about 1:1.6. In some embodiments,the molar ratio of butyllithium to diisopropylamine is about 1:1.07. Insome embodiments, the molar ratio of butyllithium to diisopropylamine isabout 1:1.5.

In certain embodiments, the molar ratio of butyllithium todiisopropylamine is from about 1:1.04 to about 1:1.1, from about 1:1.05to about 1:1.1, from about 1:1.06 to about 1:1.1, from about 1:1.07 toabout 1:1.1, from about 1:1.08 to about 1:1.1, from about 1:1.09 toabout 1:1, from about 1:1.04 to about 1:1.09, from about 1:1.04 to about1:1.08, from about 1:1.04 to about 1:1.07, from about 1:1.04 to about1:1.06, from about 1:1.04 to about 1:1.05, from about 1:1.05 to about1:1.09, from about 1:1.05 to about 1:1.08, from about 1:1.05 to about1:1.07, from about 1:1.05 to about 1:1.06, from about 1:1.06 to about1:1.09, from about 1:1.06 to about 1:1.08, from about 1:1.06 to about1:1.07, from about 1:1.07 to about 1:1.09, from about 1:1.07 to about1:1.08, or from about 1:1.08 to about 1:1.09. In some embodiments, themolar ratio of butyllithium to diisopropylamine is from about 1:1.06 toabout 1:1.07.

In certain embodiments, contacting diisopropylamine with butyllithium isconducted at a temperature of ≤0° C., ≤−5° C., ≤−10° C., ≤−15° C., or≤−20° C. In some embodiments, contacting diisopropylamine withbutyllithium is conducted at a temperature of ≤−5° C.

In certain embodiments, contacting diisopropylamine with butyllithium isconducted in tetrahydrofuran (THF).

In certain embodiments, lithium diisopropylamide is prepared before step(a), for example, before contacting ethyl isobutyrate with1-bromo-5-chloropentane.

In certain embodiments, lithium diisopropylamide is prepared in situduring step (a), for example, while contacting ethyl isobutyrate with1-bromo-5-chloropentane. In some embodiments, when lithiumdiisopropylamide is prepared in situ during step (a), the molar ratio ofthe substituted 5-chloropentane to ethyl isobutyrate to butyllithium todiisopropylamine is about 1:1.1:1.2:1.26, about 1:1.1:1.15:1.75, about1:1.1:1.24:1.3, about 1:1.1:1.2:1.29, about 1:1.1:1.2:1.28, or about1:1-1.25:1.15-1.2:1.25-1.75. In some embodiments, when lithiumdiisopropylamide is prepared in situ during step (a), the molar ratio ofthe substituted 5-chloropentane to ethyl isobutyrate to butyllithium todiisopropylamine is about 1:1.1:1.2:1.28.

In some embodiments, the substituted 5-chloropentane is1-bromo-5-chloropentane.

Synthesis of a Compound of Formula (II)—Step (b)

In various embodiments, the synthesis of a compound of formula (II):

wherein X is Br or I, generally comprises contacting the compound offormula (I) with a salt of formula [M]⁺[X]⁻.

In certain embodiments, in step (b), contacting the compound of formula(I) with a salt of formula [M]⁺[X]⁻, is conducted in a solventcomprising one or more of acetone, 2-butanone, methyl isobutyl ketone,THF and 3-pentanone, wherein M is selected from the group consisting ofLi, Na, and K, and X is selected from the group consisting of Br and I.

In certain embodiments, in step (b), the solvent comprises less thanabout 3.5% by weight water, less than about 3% by weight water, lessthan about 2.5% by weight water, less than about 2% by weight water,less than about 1.5% by weight water, less than about 1% by weightwater, or less than about 0.5% by weight water. In some embodiments, instep (b), the solvent comprises less than less than about 3% by weightwater.

In certain embodiments, in step (b), contacting the compound of formula(I) with the salt of formula [M]⁺[X]⁻ comprises contacting the compoundof formula (I) with about 1 molar equivalent, about 1.05 molarequivalents, about 1.1 molar equivalents, about 1.15 molar equivalents,about 1.2 molar equivalents, or about 1.25 molar equivalents of the saltof formula [M]⁺[X]⁻ based on the molar amount of the compound of formula(I). In certain embodiments, in step (b), contacting the compound offormula (I) with the salt of formula [M]⁺[X]⁻ comprises contacting thecompound of formula (I) with about 1.1 molar equivalents of the salt offormula [M]⁺[X]⁻ based on the molar amount of the compound of formula(I).

In certain embodiments, in step (b), contacting the compound of formula(I) with the salt of formula [M]⁺[X]⁻ is conducted at a temperature inthe range of from about 75° C. to about 85° C., from about 76° C. toabout 85° C., from about 77° C. to about 85° C., from about 78° C. toabout 85° C., from about 79° C. to about 85° C., from about 80° C. toabout 85° C., from about 81° C. to about 85° C., from about 82° C. toabout 85° C., from about 83° C. to about 85° C., from about 84° C. toabout 85° C., from about 75° C. to about 84° C., from about 75° C. toabout 83° C., from about 75° C. to about 82° C., from about 75° C. toabout 81° C., from about 75° C. to about 80° C., from about 75° C. toabout 79° C., from about 75° C. to about 78° C., from about 75° C. toabout 77° C., from about 75° C. to about 76° C., from about 76° C. toabout 84° C., from about 76° C. to about 83° C., from about 76° C. toabout 82° C., from about 76° C. to about 81° C., from about 76° C. toabout 80° C., from about 76° C. to about 79° C., from about 76° C. toabout 78° C., from about 76° C. to about 77° C., from about 77° C. toabout 84° C., from about 77° C. to about 83° C., from about 77° C. toabout 82° C., from about 77° C. to about 81° C., from about 77° C. toabout 80° C., from about 77° C. to about 79° C., from about 77° C. toabout 78° C., from about 78° C. to about 84° C., from about 78° C. toabout 83° C., from about 78° C. to about 82° C., from about 78° C. toabout 81° C., from about 78° C. to about 80° C., from about 78° C. toabout 79° C., from about 79° C. to about 84° C., from about 79° C. toabout 83° C., from about 79° C. to about 82° C., from about 79° C. toabout 81° C., from about 79° C. to about 80° C., from about 80° C. toabout 84° C., from about 80° C. to about 83° C., from about 80° C. toabout 82° C., from about 80° C. to about 81° C., from about 81° C. toabout 84° C., from about 81° C. to about 83° C., from about 81° C. toabout 82° C., from about 82° C. to about 84° C., from about 82° C. toabout 83° C., or from about 83° C. to about 84° C. In some embodiments,in step (b), contacting the compound of formula (I) with the salt offormula [M]⁺[X]⁻ is conducted at a temperature in the range of fromabout 78° C. to about 82° C.

In certain embodiments, in step (b), the salt of formula [M]⁺[X]⁻ isselected from the group consisting of lithium bromide (LiBr), lithiumiodide (LiI), potassium bromide (KBr), potassium iodide (KI), sodiumbromide (NaBr) and sodium iodide (NaI). In some embodiments, in step(b), the salt of formula [M]⁺[X]⁻ is sodium iodide.

Synthesis of a Compound of Formula (IV)—Step (c)

In various embodiments, the synthesis of a compound of formula (IV):

generally comprises contacting the compound of formula (II) withtoluenesulfonylmethyl isocyanide in the presence of a second base toform a first intermediate, and contacting the first intermediate with anacid.

Synthesis of the First Intermediate

In various embodiments, the synthesis of the first intermediate:

generally comprises contacting the compound of formula (II) withtoluenesulfonylmethyl isocyanide in the presence of a second base.

In certain embodiments, in step (c), the second base is selected fromsodium hydride, potassium tert-butoxide, and sodium tert-pentoxide. Insome embodiments, in step (c), the second base is sodium tert-pentoxide.

In certain embodiments, in step (c), contacting the compound of formula(II) with toluenesulfonylmethyl isocyanide in the presence of sodiumtert-pentoxide to form the first intermediate is conducted at atemperature in a range of from about −20° C. to about 10° C., from about−10° C. to about 10° C., from about 0° C. to about 10° C., from about−20° C. to about 0° C., from about −20° C. to about −10° C., or fromabout −10° C. to about 0° C. In certain embodiments, in step (c),contacting the compound of formula (II) with toluenesulfonylmethylisocyanide in the presence of sodium tert-pentoxide to form the firstintermediate is conducted at a temperature in a range of from about −20°C. to about 10° C. In certain embodiments, in step (c), contacting thecompound of formula (II) with toluenesulfonylmethyl isocyanide in thepresence of sodium tert-pentoxide to form the first intermediate isconducted at a temperature in a range of from about −15° C. to about 0°C.

In certain embodiments, in step (c), contacting the compound of formula(II) with toluenesulfonylmethyl isocyanide in the presence of a secondbase to form the first intermediate is conducted at a temperature ofabout −20° C., about −15° C., about −10° C., about −5° C., or about 0°C.

In certain embodiments, in step (c), the molar ratio of the compound offormula (II) to toluenesulfonylmethyl isocyanide is about 1.7:1, about1.8:1, about 1.9:1, about 2:1, about 2.1:1, or about 2.2:1. In certainembodiments, in step (c), the molar ratio of the compound of formula(II) to toluenesulfonylmethyl isocyanide is about 1.9:1.

In some embodiments, in step (c), the molar ratio of the compound offormula (II) to toluenesulfonylmethyl isocyanide to the second base isabout 1.9:1.0:2.1. In some embodiments, in step (c), the molar ratio ofthe compound of formula (II) to toluenesulfonylmethyl isocyanide to thesecond base is about 1.9:1.0:2.2.

In some embodiments, in step (c), the molar ratio of the compound offormula (II) to toluenesulfonylmethyl isocyanide to sodiumtert-pentoxide is about 1.9:1.0:2.1. In some embodiments, in step (c),the molar ratio of the compound of formula (II) to toluenesulfonylmethylisocyanide to sodium tert-pentoxide is about 1.9:1.0:2.2.

In certain embodiments, in step (c), contacting the compound of formula(II) with toluenesulfonylmethyl isocyanide is conducted in a solventcomprising dimethylacetamide or that is dimethylacetamide.

Synthesis of a Compound of Formula (IV)

In various embodiments, the synthesis of a compound of formula (IV):

generally comprises contacting the first intermediate with an acid.

In certain embodiments, in step (c), contacting the first intermediatewith an acid is conducted at a temperature in a range of from about −15°C. to about 35° C., from about −10° C. to about 35° C., from about −5°C. to about 35° C., from about 0° C. to about 35° C., from about 5° C.to about 35° C., from about 10° C. to about 35° C., from about 15° C. toabout 35° C., from about 20° C. to about 35° C., from about 25° C. toabout 35° C., from about 30° C. to about 35° C., from about −15° C. toabout 30° C., from about −15° C. to about 25° C., from about −15° C. toabout 20° C., from about −15° C. to about 15° C., from about −15° C. toabout 10° C., from about −15° C. to about 5° C., from about −15° C. toabout 0° C., from about −15° C. to about −5° C., from about −15° C. toabout −10° C., from about −10° C. to about 30° C., from about −10° C. toabout 25° C., from about −10° C. to about 20° C., from about −10° C. toabout 15° C., from about −10° C. to about 10° C., from about −10° C. toabout 5° C., from about −10° C. to about 10° C., from about −10° C. toabout −5° C., from about −5° C. to about 30° C., from about −5° C. toabout 25° C., from about −5° C. to about 20° C., from about −5° C. toabout 15° C., from about −5° C. to about 10° C., from about −5° C. toabout 5° C., from about −5° C. to about 0° C., from about 0° C. to about30° C., from about 0° C. to about 25° C., from about 0° C. to about 20°C., from about 0° C. to about 15° C., from about 0° C. to about 10° C.,from about 0° C. to about 5° C., from about 5° C. to about 30° C., fromabout 5° C. to about 25° C., from about 5° C. to about 20° C., fromabout 5° C. to about 15° C., from about 5° C. to about 10° C., fromabout 10° C. to about 30° C., from about 10° C. to about 25° C., fromabout 10° C. to about 20° C., from about 10° C. to about 15° C., fromabout 15° C. to about 30° C., from about 15° C. to about 25° C., fromabout 15° C. to about 20° C., from about 20° C. to about 30° C., fromabout 20° C. to about 25° C., or from about 25° C. to about 30° C. Insome embodiments, in step (c), contacting the first intermediate with anacid is conducted at a temperature in a range of from about −10° C. toabout 35° C. In some embodiments, in step (c), contacting the firstintermediate with an acid is conducted at a temperature in a range offrom about −15° C. to about 25° C. In some embodiments, in step (c),contacting the first intermediate with an acid is conducted at atemperature in a range of from about 10° C. to about 25° C.

In certain embodiments, in step (c), the acid is hydrochloric acid.

Synthesis of a Compound of Formula (V)—Step (d)

In various embodiments the synthesis of a compound of formula (V):

generally comprises contacting the compound of formula (IV) with areducing agent to form a second intermediate, and contacting the secondintermediate with a hydrolyzing base.

Synthesis of the Second Intermediate

In various embodiments, the synthesis of the second intermediate:

generally comprises contacting the compound of formula (IV) with areducing agent.

In certain embodiments, in step (d), the reducing agent is selected fromthe group consisting of sodium borohydride, sodium cyanoborohydride,cerium borohydride, zinc borohydride and diisobutylaluminum hydride. Insome embodiments, the reducing agent is sodium borohydride.

In certain embodiments, in step (d), contacting the compound of formula(IV) with a reducing agent comprises contacting the compound of formula(IV) with about 0.25 molar equivalents, about 0.3 molar equivalents,about 0.35 molar equivalents, about 0.4 molar equivalents, about 0.45,about 0.5 molar equivalents, about 0.6 molar equivalents, about 0.7molar equivalents, about 0.8 molar equivalents, about 0.9 molarequivalents, about 1.0 molar equivalents, about 1.1 molar equivalents,about 1.2 molar equivalents, about 1.3 molar equivalents, about 1.4molar equivalents, or about 1.5 molar equivalents of the reducing agentbased on the molar amount of the compound of formula (IV). In someembodiments, in step (d), contacting the compound of formula (IV) with areducing agent comprises contacting the compound of formula (IV) withabout 0.35 molar equivalents of the reducing agent based on the molaramount of the compound of formula (IV).

In certain embodiments, in step (c), contacting the compound of formula(IV) with a reducing agent is conducted at a temperature in a range offrom about 5° C. to about 30° C., from about 10° C. to about 30° C.,from about 15° C. to about 30° C., from about 20° C. to about 30° C.,from about 25° C. to about 30° C., from about 5° C. to about 25° C.,from about 5° C. to about 20° C., from about 5° C. to about 15° C., fromabout 5° C. to about 10° C., from about 10° C. to about 25° C., fromabout 10° C. to about 20° C., from about 10° C. to about 15° C., fromabout 15° C. to about 25° C., from about 15° C. to about 20° C., or fromabout 20° C. to about 25° C.

In certain embodiments, in step (c), contacting the compound of formula(IV) with a reducing agent is conducted at a temperature of about 5° C.,about 10° C., about 15° C., about 20° C., about 25° C., or about 30° C.

Synthesis of a Compound of Formula (V)

In various embodiments, the synthesis of a compound of formula (V):

generally comprises contacting the second intermediate with ahydrolysing base.

In certain embodiments, in step (d), the concentration of thehydrolyzing base is about 20% w/w, about 25% w/w, about 30% w/w, about35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, orabout 60% w/w. In some embodiments, in step (d), the concentration ofthe hydrolyzing base is about 50% w/w.

In certain embodiments, in step (d), contacting the second intermediatewith a hydrolyzing base to form a compound of formula (V) is conductedin a solution. In some embodiments, in step (d), the method furthercomprises adjusting the pH of the solution comprising the compound offormula (V) to between about 3 to about 7.

In certain embodiments, in step (d), contacting the second intermediatewith a hydrolyzing base is conducted at a temperature in a range of fromabout 30° C. to about 60° C., from about 35° C. to about 60° C., fromabout 40° C. to about 60° C., from about 45° C. to about 60° C., fromabout 50° C. to about 60° C., from about 55° C. to about 60° C., fromabout 30° C. to about 55° C., from about 30° C. to about 50° C., fromabout 30° C. to about 45° C., from about 30° C. to about 40° C., fromabout 30° C. to about 35° C., from about 35° C. to about 55° C., fromabout 35° C. to about 50° C., from about 35° C. to about 45° C., fromabout 35° C. to about 40° C., from about 40° C. to about 55° C., fromabout 40° C. to about 50° C., from about 40° C. to about 45° C., fromabout 45° C. to about 55° C., from about 45° C. to about 50° C., or fromabout 50° C. to about 60° C.

In certain embodiments, in step (d), contacting the second intermediatewith a hydrolyzing base is conducted at a temperature of about 30° C.,about 35° C., about 40° C., about 45° C., about 50° C., about 55° C., orabout 60° C. In certain embodiments, in step (d), contacting the secondintermediate with a hydrolyzing base is conducted at a temperature ofabout 50° C.

In certain embodiments, in step (d), the hydrolyzing base is sodiumhydroxide.

In certain embodiments, in step (d), contacting the compound of formula(IV) with a reducing agent to form a second intermediate, and contactingthe second intermediate with a hydrolyzing base to form a compound offormula (V) is conducted in a single reaction vessel.

In some embodiments of the present aspect, the methods can include:

(a) contacting ethyl isobutyrate with 1-bromo-5-chloropentane in thepresence of a first base to form a compound of formula (I):

(b) contacting the compound of formula (I) with sodium iodide to form acompound of formula (IIa):

(c) contacting the compound of formula (IIa) with toluenesulfonylmethylisocyanide in the presence of a second base to form a firstintermediate, and contacting the first intermediate with an acid to forma compound of formula (IV):

and

(d) contacting the compound of formula (IV) with a reducing agent toform a second intermediate, and contacting the second intermediate witha hydrolyzing base to form a compound of formula (V).

In some embodiments of the invention, the method further comprises:

(e) purifying the compound of formula (V) to provide a pharmaceuticalmaterial comprising a purified amount of the compound of formula (V).

In some embodiments as described above, the same conditions (e.g.,temperatures) amounts, ratios, equivalents, times, purities, and otherparameters or variables that were previously described can be equallyapplicable, for example, where “1-bromo-5-chloropentane” is substitutedfor “substituted-5-chloropentane;” “sodium iodide” is substituted for “asalt of formula [M]⁺[X]⁻; “Na” is substituted for “M;” “I” issubstituted for “X;” and a “compound of formula (IIa)” is substitutedfor a “compound of formula II.”

In addition, in certain embodiments, the concentration of1,5-dichloropentane in 1-bromo-5-chloropentane is ≤0.1%, ≤0.2%, ≤0.3%,≤0.4%, ≤0.5%, ≤0.6%, ≤0.7%, ≤0.8%, ≤0.9%, or ≤1%, as measured by GC. Insome embodiments, the concentration of 1,5-dichloropentane in1-bromo-5-chloropentane is ≤0.5%, as measured by GC.

In certain embodiments, the concentration of 1,5-dibromopentane in1-bromo-5-chloropentane is ≤0.05%, ≤0.1%, ≤0.15%, ≤0.2%, ≤0.25%, ≤0.3%,≤0.35%, ≤0.4%, ≤0.45%, ≤0.5%, ≤0.6%, ≤0.7%, ≤0.8%, ≤0.9%, or ≤1.0%, asmeasured by GC. In some embodiments, the concentration of1,5-dibromopentane in 1-bromo-5-chloropentane is ≤0.2%, as measured byGC. In some embodiments, the concentration of 1,5-dibromopentane in1-bromo-5-chloropentane is ≤1.0%, as measured by GC.

In certain embodiments, the amount of unreacted 1-bromo-5-chloropentaneremaining upon completion of step (a) is ≤0.05%, ≤0.06%, ≤0.07%, ≤0.08%,≤0.09%, ≤0.1%, ≤0.11%, ≤0.12%, ≤0.12%, ≤0.13%, ≤0.14%, ≤0.15%, ≤0.16%,≤0.17%, ≤0.18%, ≤0.19%, or ≤0.2%, as measured by GC. In someembodiments, the amount of unreacted 1-bromo-5-chloropentane remainingupon completion of step (a) is ≤0.21%, ≤0.22%, ≤0.23%, ≤0.24%, ≤0.25%,≤0.25%, ≤0.26%, ≤0.27%, ≤0.28%, ≤0.29%, ≤0.3%, ≤0.31%, ≤0.32%, ≤0.33%,≤0.34%, ≤0.35%, ≤0.36%, ≤0.37%, ≤0.38%, ≤0.39%, or ≤0.4%, as measured byGC.

In certain embodiments, a method of preparing a compound of formula (V)comprises:

(a) contacting 1-bromo-5-chloropentane with about 1.1 molar equivalentsof ethyl isobutyrate in the presence of lithium diisopropylamide at atemperature in the range of from about −20° C. to about 0° C. to form acompound of formula (I):

(b) contacting the compound of formula (I) with about 1.1 molarequivalents of sodium iodide in 2-butanone at a temperature in the rangeof from about 78° C. to about 82° C. to form a compound of formula(IIa):

(c) contacting the compound of formula (IIa) with toluenesulfonylmethylisocyanide in the presence of sodium tert-pentoxide in dimethylacetamideat a temperature in the range of from about −20° C. to about 10° C. toform a first intermediate, and contacting the first intermediate with anacid at a temperature in the range of from about −10° C. to about 35° C.to form a compound of formula (IV):

and

(d) contacting the compound of formula (IV) with about 0.35 molarequivalents of sodium borohydride to form a second intermediate, andcontacting the second intermediate with sodium hydroxide in a solutionto form a compound of formula (V).

In certain embodiments of the invention, the method further comprises:

(e) purifying the compound of formula (V) to provide a pharmaceuticalmaterial comprising a purified amount of the compound of formula (V).

In certain embodiments as described above, the same conditions (e.g.,temperatures) amounts, ratios, equivalents, times, purities, and otherparameters or variables that were previously described can be equallyapplicable, for example, where “lithium diisopropylamide” is substitutedfor “a first base;” “sodium tert-pentoxide” is substituted for “a secondbase;” “sodium borohydride” is substituted for “a reducing agent;” and“sodium hydroxide” is substituted for a hydrolyzing base.”

In addition, in certain embodiments, in step (a), contacting ethylisobutyrate with 1-bromo-5-chloropentane in the presence of lithiumdiisopropylamide is conducted at a temperature in the range of fromabout −20° C. to about 0° C., from about −15° C. to about 0° C., fromabout −10° C. to about 0° C., from about −5° C. to about 0° C., fromabout −20° C. to about −5° C., from about −20° C. to about −10° C., fromabout −20° C. to about −15° C., from about −15° C. to about −5° C., fromabout −15° C. to about −10° C., or from about −10° C. to about −5° C.

In certain embodiments, in step (b), contacting the compound of formula(I) with sodium iodide is conducted at a temperature in the range offrom about 78° C. to about 82° C., from about 78° C. to about 80° C., orfrom about 80° C. to about 82° C.

In certain embodiments, in step (c), the molar ratio of the compound offormula (IIa) to toluenesulfonylmethyl isocyanide to sodiumtert-pentoxide is about 1.9:1:2.1.

Purification of a Compound of Formula (V)—Step (e)

Various embodiments of the invention include methods for producing apharmaceutical material comprising a purified amount of a compound offormula (V):

i.e., the methods can include purifying the compound of formula (V).

In various embodiments, purifying the compound of formula (V) comprisesfiltering the compound of formula (V) in a solvent through silica gel.In some embodiments, the solvent comprises ethyl acetate. In someembodiments, the solvent is ethyl acetate.

In certain embodiments, purifying the compound of formula (V) comprisescrystallizing the compound of formula (V) to provide a crystalline formof the compound of formula (V).

In certain embodiments, purifying the compound of formula (V) comprisescontacting the compound of formula (V) with charcoal and then filteringthe charcoal. In some embodiments, contacting the compound of formula(V) with charcoal comprises contacting the compound of formula (V) witha solution, wherein the solution comprises acetonitrile and activatedcharcoal (e.g., 5% (w/w) activated charcoal).

In certain embodiments, purifying the compound of formula (V) comprisesrecrystallizing the crystalline form of the compound of formula (V) toprovide a pharmaceutical material comprising a purified amount of thecompound of formula (V).

In various embodiments, purifying the compound of formula (V) comprises:

(f) adjusting the pH of the solution comprising the compound of formula(V) to about 5 to about 6;

(g) extracting the compound of formula (V) from the solution usingmethyl tert-butyl ether to provide a methyl tert-butyl ether solutioncomprising the compound of formula (V);

(h) exchanging the methyl tert-butyl ether of the methyl tert-butylether solution with ethyl acetate to provide an ethyl acetate solutioncomprising the compound of formula (V);

(i) filtering the ethyl acetate solution comprising the compound offormula (V) through silica gel;

(j) crystallizing the compound of formula (V) using ethyl acetate andwater to provide a crystalline form of the compound of formula (V); and

(k) recrystallizing the crystalline form of the compound of formula (V)using ethyl acetate and water to provide a pharmaceutical materialcomprising a purified amount of the compound of formula (V).

In certain embodiments, in step (g), extracting the compound of formula(V) from the solution using methyl tert-butyl ether is conducted at atemperature less than or equal to about 5° C., about 10° C., about 15°C., about 20° C., about 25° C., about 30° C., about 35° C., about 40°C., about 45° C., about 50° C., or about 55° C. In certain embodiments,in step (g), extracting the compound of formula (V) from the solutionusing methyl tert-butyl ether is conducted at a temperature less than orequal to about 15° C. In certain embodiments, in step (g), extractingthe compound of formula (V) from the solution using methyl tert-butylether is conducted at a temperature less than or equal to about 50° C.

In certain embodiments, in step (j), crystallizing the compound offormula (V) using ethyl acetate and water is conducted over atemperature range of about 60° C. to about −10° C., about 55° C. toabout −10° C., about 50° C. to about −10° C., about 45° C. to about −10°C., about 40° C. to about −10° C., about 35° C. to about −10° C., about30° C. to about −10° C., about 25° C. to about −10° C., about 20° C. toabout −10° C., about 15° C. to about −10° C., about 10° C. to about −10°C., about 5° C. to about −10° C., about 0° C. to about −10° C., about−5° C. to about −10° C., about 60° C. to about −5° C., about 55° C. toabout −5° C., about 50° C. to about −5° C., about 45° C. to about −5°C., about 40° C. to about −5° C., about 35° C. to about −5° C., about30° C. to about −5° C., about 25° C. to about −5° C., about 20° C. toabout −5° C., about 15° C. to about −5° C., about 10° C. to about −5°C., about 5° C. to about −5° C., about 0° C. to about −5° C., about 60°C. to about 0° C., about 55° C. to about 0° C., about 50° C. to about 0°C., about 45° C. to about 0° C., about 40° C. to about 0° C., about 35°C. to about 0° C., about 30° C. to about 0° C., about 25° C. to about 0°C., about 20° C. to about 0° C., about 15° C. to about 0° C., about 10°C. to about 0° C., about 5° C. to about 0° C., about 60° C. to about 5°C., about 55° C. to about 5° C., about 50° C. to about 5° C., about 45°C. to about 5° C., about 40° C. to about 5° C., about 35° C. to about 5°C., about 30° C. to about 5° C., about 25° C. to about 5° C., about 20°C. to about 5° C., about 15° C. to about 5° C., about 10° C. to about 5°C., about 60° C. to about 10° C., about 55° C. to about 10° C., about50° C. to about 10° C., about 45° C. to about 10° C., about 40° C. toabout 10° C., about 35° C. to about 10° C., about 30° C. to about 10°C., about 25° C. to about 10° C., about 20° C. to about 10° C., about15° C. to about 10° C., about 60° C. to about 15° C., about 55° C. toabout 15° C., about 50° C. to about 15° C., about 45° C. to about 15°C., about 40° C. to about 15° C., about 35° C. to about 15° C., about30° C. to about 15° C., about 25° C. to about 15° C., about 20° C. toabout 15° C., about 60° C. to about 20° C., about 55° C. to about 20°C., about 50° C. to about 20° C., about 45° C. to about 20° C., about40° C. to about 20° C., about 35° C. to about 20° C., about 30° C. toabout 20° C., about 25° C. to about 20° C., about 60° C. to about 25°C., about 55° C. to about 25° C., about 50° C. to about 25° C., about45° C. to about 25° C., about 40° C. to about 25° C., about 35° C. toabout 25° C., about 30° C. to about 25° C., about 60° C. to about 30°C., about 55° C. to about 30° C., about 50° C. to about 30° C., about45° C. to about 30° C., about 60° C. to about 35° C., about 55° C. toabout 35° C., about 50° C. to about 35° C., about 45° C. to about 35°C., about 40° C. to about 35° C., about 60° C. to about 40° C., about55° C. to about 40° C., about 50° C. to about 40° C., about 45° C. toabout 40° C., about 60° C. to about 45° C., about 55° C. to about 45°C., about 50° C. to about 45° C., about 60° C. to about 50° C., about55° C. to about 50° C., or about 60° C. to about 55° C. In certainembodiments, in step (j), crystallizing the compound of formula (V)using ethyl acetate and water is conducted over a temperature range ofabout 50° C. to about −5° C.

In certain embodiments, in step (k), recrystallizing the crystallineform of the compound of formula (V) using ethyl acetate and water isconducted over a temperature range of about 70° C. to about 5° C., about65° C. to about 5° C., about 60° C. to about 5° C., about 55° C. toabout 5° C., about 50° C. to about 5° C., about 45° C. to about 5° C.,about 40° C. to about 5° C., about 35° C. to about 5° C., about 30° C.to about 5° C., about 25° C. to about 5° C., about 20° C. to about 5°C., about 15° C. to about 5° C., about 10° C. to about 5° C., about 70°C. to about 10° C., about 65° C. to about 10° C., about 60° C. to about10° C., about 55° C. to about 10° C., about 50° C. to about 10° C.,about 45° C. to about 10° C., about 40° C. to about 10° C., about 35° C.to about 10° C., about 30° C. to about 10° C., about 25° C. to about 10°C., about 20° C. to about 10° C., about 15° C. to about 10° C., about70° C. to about 15° C., about 65° C. to about 15° C., about 60° C. toabout 15° C., about 55° C. to about 15° C., about 50° C. to about 15°C., about 45° C. to about 15° C., about 40° C. to about 15° C., about35° C. to about 15° C., about 30° C. to about 15° C., about 25° C. toabout 15° C., about 20° C. to about 15° C., about 70° C. to about 20°C., about 65° C. to about 20° C., about 60° C. to about 20° C., about55° C. to about 20° C., about 50° C. to about 20° C., about 45° C. toabout 20° C., about 40° C. to about 20° C., about 35° C. to about 20°C., about 30° C. to about 20° C., about 25° C. to about 20° C., about70° C. to about 25° C., about 65° C. to about 25° C., about 60° C. toabout 25° C., about 55° C. to about 25° C., about 50° C. to about 25°C., about 45° C. to about 25° C., about 40° C. to about 25° C., about35° C. to about 25° C., about 30° C. to about 25° C., about 70° C. toabout 30° C., about 65° C. to about 30° C., about 60° C. to about 30°C., about 55° C. to about 30° C., about 50° C. to about 30° C., about45° C. to about 30° C., about 40° C. to about 30° C., about 35° C. toabout 30° C., about 70° C. to about 35° C., about 65° C. to about 35°C., about 60° C. to about 35° C., about 55° C. to about 35° C., about50° C. to about 35° C., about 45° C. to about 35° C., about 40° C. toabout 35° C., about 70° C. to about 40° C., about 65° C. to about 40°C., about 60° C. to about 40° C., about 55° C. to about 40° C., about50° C. to about 40° C., about 45° C. to about 40° C., about 70° C. toabout 45° C., about 65° C. to about 45° C., about 60° C. to about 45°C., about 55° C. to about 45° C., about 50° C. to about 45° C., about70° C. to about 50° C., about 65° C. to about 50° C., about 60° C. toabout 50° C., about 55° C. to about 50° C., about 70° C. to about 55°C., about 65° C. to about 55° C., about 60° C. to about 55° C., about70° C. to about 60° C., about 65° C. to about 60° C., or about 70° C. toabout 65° C. In certain embodiments, in step (k), recrystallizing thecrystalline form of the compound of formula (V) using ethyl acetate andwater is conducted over a temperature range of about 70° C. to about 5°C.

In certain embodiments, purifying the compound of formula (V) comprises:

(l) dissolving the crystalline form of the compound of formula (V) inacetonitrile, thereby forming a solution;

(m) contacting the solution with charcoal;

(n) filtering the charcoal to provide a purified solution comprising thecompound of formula (V); and

(o) crystallizing the compound of formula (V) from the purified solutionto provide a pharmaceutical material comprising a purified amount of thecompound of formula (V).

It should be understood that, in various embodiments, the above steps(l)-(o) can be conducted after or without conducting steps (f)-(k).

Crystallization of the Compound of Formula (V)

In various embodiments, purifying the compound of formula (V) comprisescrystallizing the compound of formula (V) from a solvent or a mixture ofsolvents, for example, ethyl acetate and water.

In certain embodiments, the concentration of water in the mixture ofsolvents comprising ethyl acetate and water is about 0.5% (w/w), about0.6% (w/w), about 0.75% (w/w), about 0.9% (w/w), about 1.05% (w/w),about 1.2% (w/w), about 1.35% (w/w), about 1.4% (w/w), or about 1.5%(w/w). In some embodiments, the concentration of water in the mixture ofsolvents comprising ethyl acetate and water is about 1.05% (w/w).

In certain embodiments, the concentration of water in the mixture ofsolvents comprising ethyl acetate and water is from about 0.5% (w/w) toabout 1.5% (w/w), from about 0.5% (w/w) to about 1.4% (w/w), from about0.5% (w/w) to about 1.35% (w/w), from about 0.5% (w/w) to about 1.2%(w/w), from about 0.5% (w/w) to about 1.05% (w/w), from about 0.5% (w/w)to about 0.9% (w/w), from about 0.5% (w/w) to about 0.75% (w/w), fromabout 0.5% (w/w) to about 0.6% (w/w), from about 0.6% (w/w) to about1.5% (w/w), from about 0.6% (w/w) to about 1.4% (w/w), from about 0.6%(w/w) to about 1.35% (w/w), from about 0.6% (w/w) to about 1.2% (w/w),from about 0.6% (w/w) to about 1.05% (w/w), from about 0.6% (w/w) toabout 0.9% (w/w), from about 0.6% (w/w) to about 0.75% (w/w), from about0.75% (w/w) to about 1.5% (w/w), from about 0.75% (w/w) to about 1.4%(w/w), from about 0.75% (w/w) to about 1.35% (w/w), from about 0.75%(w/w) to about 1.2% (w/w), from about 0.75% (w/w) to about 1.05% (w/w),from about 0.75% (w/w) to about 0.9% (w/w), from about 0.9% (w/w) toabout 1.5% (w/w), from about 0.9% (w/w) to about 1.35% (w/w), from about0.9% (w/w) to about 1.2% (w/w), from about 0.9% (w/w) to about 1.05%(w/w), from about 1.05% (w/w) to about 1.5% (w/w), from about 1.05%(w/w) to about 1.35% (w/w), from about 1.05% (w/w) to about 1.2% (w/w),from about 1.2% (w/w) to about 1.5% (w/w), from about 1.2% (w/w) toabout 1.5% (w/w), from about 1.2% (w/w) to about 1.35% (w/w), or fromabout 1.35% (w/w) to about 1.5% (w/w). In some embodiments, theconcentration of water in the mixture of solvents comprising ethylacetate and water is from about 0.6% (w/w) to about 1.4% (w/w). In someembodiments, the concentration of water in the mixture of solventscomprising ethyl acetate and water is from about 0.75% (w/w) to about1.35% (w/w).

In various embodiments, crystallizing the compound of formula (V) from amixture comprising the compound of formula (V), ethyl acetate and watercomprises:

-   -   (1) cooling the mixture from a first temperature (T¹) to a        second temperature (T²), wherein T¹ is from about 40° C. to        about 60° C., T² is from about 15° C. to about 30° C., and the        mixture is cooled from T¹ to T² at a rate of from about 10°        C./hour to about 20° C./hour;    -   (2) holding the mixture at T² for at least 3 hours;    -   (3) cooling the mixture from T² to a third temperature (T³),        wherein T³ is from about −5° C. to about 10° C. and the mixture        is cooled from T² to T³ at a rate of from about 5° C./hour to        about 15° C./hour; and    -   (4) holding the mixture at T³ for at least 3 hours,        thereby producing a crystalline form of the compound of formula        (V).

In certain embodiments, in crystallization step (1), T¹ is from about40° C. to about 60° C., from about 45° C. to about 60° C., from about50° C. to about 60° C., from about 55° C. to about 60° C., from about40° C. to about 55° C., from about 40° C. to about 50° C., from about40° C. to about 45° C., from about 45° C. to about 55° C., from about45° C. to about 50° C., or from about 50° C. to about 55° C. In someembodiments, in crystallization step (1), T¹ is from about 40° C. toabout 60° C. In some embodiments, in crystallization step (1), T¹ isfrom about 45° C. to about 55° C.

In certain embodiments, in crystallization step (1), T¹ is about 40° C.,about 45° C., about 50° C., about 55° C., or about 60° C. In someembodiments, in crystallization step (1), T¹ is about 50° C.

In certain embodiments, in crystallization step (1), T² is from about15° C. to about 30° C., from about 20° C. to about 30° C., from about25° C. to about 30° C., from about 15° C. to about 25° C., from about15° C. to about 20° C., or from about 20° C. to about 25° C. In someembodiments, in crystallization step (i), T² is from about 15° C. toabout 30° C. In some embodiments, in crystallization step (1), T² isfrom about 20° C. to about 25° C.

In certain embodiments, in crystallization step (1), T² is about 15° C.,about 16° C., about 17° C., about 18° C., about 19° C., about 20° C.,about 21° C., about 22° C., about 23° C., about 24° C., about 25° C.,about 26° C., about 27° C., about 28° C., about 29° C., or about 30° C.In some embodiments, in crystallization step (1), T² is about 22° C.

In certain embodiments, in crystallization step (1), the mixture iscooled from T¹ to T² at a rate of from about 10° C./hour to about 20°C./hour, from about 12° C./hour to about 20° C./hour, from about 14°C./hour to about 20° C./hour, from about 16° C./hour to about 20°C./hour, from about 18° C./hour to about 20° C./hour, from about 10°C./hour to about 18° C./hour, from about 10° C./hour to about 16°C./hour, from about 10° C./hour to about 14° C./hour, from about 10°C./hour to about 12° C./hour, from about 12° C./hour to about 18°C./hour, from about 12° C./hour to about 16° C./hour, from about 12°C./hour to about 14° C./hour, from about 14° C./hour to about 18°C./hour, from about 14° C./hour to about 16° C./hour, or from about 16°C./hour to about 18° C./hour. In some embodiments, the mixture is cooledfrom T¹ to T² at a rate of from about 10° C./hour to about 20° C./hour.In some embodiments, the mixture is cooled from T¹ to T² at a rate offrom about 10° C./hour to about 12° C./hour.

In certain embodiments, in crystallization step (1), the mixture iscooled from T¹ to T² at a rate of about 10° C./hour, about 11° C./hour,about 12° C./hour, about 13° C./hour, about 14° C./hour, about 15°C./hour, about 16° C./hour, about 17° C./hour, about 18° C./hour, about19° C./hour, or about 20° C./hour. In certain embodiments, incrystallization step (1), the mixture is cooled from T¹ to T² at a rateof about 11° C./hour.

In certain embodiments, in crystallization step (2), the mixture is heldat T² for at least 3 hours, at least 3.5 hours, at least 4 hours, atleast 4.5 hours, at least 5 hours, at least 5.5 hours, at least 6 hours,at least 6.5 hours, at least 7 hours, at least 7.5 hours, at least 8hours, at least 8.5 hours, at least 9 hours, at least 9.5 hours, or atleast 10 hours. In some embodiments, in crystallization step (2), themixture is held at T² for at least 6 hours.

In certain embodiments, in crystallization step (2), the mixture is heldat T² for no greater than 3 hours, no greater than 3.5 hours, no greaterthan 4 hours, no greater than 4.5 hours, no greater than 5 hours, nogreater than 5.5 hours, no greater than 6 hours, no greater than 6.5hours, no greater than 7 hours, no greater than 7.5 hours, no greaterthan 8 hours, no greater than 8.5 hours, no greater than 9 hours, nogreater than 9.5 hours, no greater than 10 hours, no greater than 10.5hours, no greater than 11 hours, no greater than 11.5 hours, no greaterthan 12 hours, no greater than 16 hours, no greater than 20 hours, or nogreater than 24 hours. In some embodiments, in crystallization step (2),the mixture is held at T² for no greater than 6 hours.

In certain embodiments, in crystallization step (3), T³ is from about−5° C. to about 10° C., from about 0° C. to about 10° C., from about 5°C. to about 10° C., from about −5° C. to about 5° C., from about −5° C.to about 0° C., or from about 0° C. to about 5° C. In some embodiments,T³ is from about −5° C. to about 10° C. In some embodiments, T³ is fromabout −5° C. to about 5° C.

In certain embodiments, in crystallization step (3), T³ is about −5° C.,about 0° C., about 5° C., or about 10° C. In some embodiments, incrystallization step (3), T³ is about 0° C.

In certain embodiments, in crystallization step (3), the mixture iscooled from T² to T³ at a rate of from about 5° C./hour to about 15°C./hour, from about 7° C./hour to about 15° C./hour, from about 9°C./hour to about 15° C./hour, from about 11° C./hour to about 15°C./hour, from about 13° C./hour to about 15° C./hour, from about 5°C./hour to about 13° C./hour, from about 5° C./hour to about 11°C./hour, from about 5° C./hour to about 9° C./hour, from about 5°C./hour to about 7° C./hour, from about 7° C./hour to about 13° C./hour,from about 7° C./hour to about 11° C./hour, from about 7° C./hour toabout 9° C./hour, from about 9° C./hour to about 13° C./hour, from about9° C./hour to about 11° C./hour, or from about 11° C./hour to about 13°C./hour. In some embodiments, in crystallization step (3), the mixtureis cooled from T² to T³ at a rate of from about 5° C./hour to about 15°C./hour. In some embodiments, in crystallization step (3), the mixtureis cooled from T² to T³ at a rate of from about 7° C./hour to about 13°C./hour.

In certain embodiments, in crystallization step (3), the mixture iscooled from T² to T³ at a rate of about 5° C./hour, about 6° C./hour,about 7° C./hour, about 8° C./hour, about 9° C./hour, about 10° C./hour,about 11° C./hour, about 12° C./hour, about 13° C./hour, about 14°C./hour, or about 15° C./hour. In some embodiments, in crystallizationstep (3), the mixture is cooled from T² to T³ at a rate of about 11°C./hour.

In certain embodiments, in crystallization step (4), the mixture is heldat T³ for at least 3 hours, at least 3.5 hours, at least 4 hours, atleast 4.5 hours, at least 5 hours, at least 5.5 hours, at least 6 hours,at least 6.5 hours, at least 7 hours, at least 7.5 hours, at least 8hours, at least 8.5 hours, at least 9 hours, at least 9.5 hours, or atleast 10 hours. In some embodiments, in crystallization step (4), themixture is held at T³ for at least 6 hours.

In certain embodiments, in crystallization step (4), the mixture is heldat T³ for no greater than 3 hours, no greater than 3.5 hours, no greaterthan 4 hours, no greater than 4.5 hours, no greater than 5 hours, nogreater than 5.5 hours, no greater than 6 hours, no greater than 6.5hours, no greater than 7 hours, no greater than 7.5 hours, no greaterthan 8 hours, no greater than 8.5 hours, no greater than 9 hours, nogreater than 9.5 hours, no greater than 10 hours, no greater than 10.5hours, no greater than 11 hours, no greater than 11.5 hours, no greaterthan 12 hours, no greater than 16 hours, no greater than 20 hours, or nogreater than 24 hours. In some embodiments, in crystallization step (4),the mixture is held at T³ for no greater than 10 hours.

In certain embodiments, crystallizing the compound of formula (V) from amixture comprising the compound of formula (V), ethyl acetate and waterfurther comprises seeding the mixture with an amount of a crystallineform of the compound of formula (V) prior to crystallization step (1),during crystallization step (1), during crystallization step (2), duringcrystallization step (3), during crystallization step (4), or anycombination thereof, in order to facilitate the crystallization of thecompound of formula (V).

In certain embodiments, the amount of seed added to the mixture is about0.001 kg/kg, about 0.0012 kg/kg, about 0.0014 kg/kg, about 0.0016 kg/kg,about 0.0018 kg/kg, or about 0.002 kg/kg, based on the weight of seedper kilogram of the compound of formula (IV) produced in step (c). Insome embodiments, the amount of seed added to the mixture is about0.0014 kg/kg, based on the weight of seed per kilogram of the compoundof formula (IV) produced in step (c).

In certain embodiments, the crystalline form of the compound of formula(V) added as seed to the mixture may be a crystalline form of thecompound of formula (V) as characterized herein, for example, by anX-ray powder diffraction pattern or peak(s), and/or other characteristicproperties of the crystalline form of bempedoic acid.

In certain embodiments, crystallizing the compound of formula (V) from amixture comprising the compound of formula (V), ethyl acetate and watercomprises filtration of the compound of formula (V).

In certain embodiments, filtering the crystalline form of the compoundof formula (V) occurs at a temperature of from about −20° C. to about 5°C., from about −15° C. to about 5° C., from about −10° C. to about 5°C., from about −5° C. to about 5° C., from about 0° C. to about 5° C.,from about −20° C. to about 0° C., from about −20° C. to about −5° C.,from about −20° C. to about −10° C., from about −20° C. to about −15°C., from about −15° C. to about 5° C., from about −15° C. to about 0°C., from about −15° C. to about −5° C., from about −15° C. to about −10°C., from about −10° C. to about 5° C., from about −10° C. to about 0°C., from about −10° C. to about −5° C., from about −5° C. to about 5°C., from about −5° C. to about 0° C., or from about 0° C. to about 5° C.In some embodiments, filtering the crystalline form of the compound offormula (V) occurs at a temperature of from about −20° C. to about −5°C. In some embodiments, filtering the crystalline form of the compoundof formula (V) occurs at a temperature of about −5° C. to about 5° C.

In certain embodiments, filtering the crystalline form of the compoundof formula (V) occurs at a temperature of about −20° C., about −15° C.,about −10° C., about −5° C., about 0° C., or about 5° C. In someembodiments, filtering the crystalline form of the compound of formula(V) occurs at a temperature of about −10° C., about −5° C., or about 0°C.

In certain embodiments, filtration further comprises washing. In certainembodiments, washing comprises washing the crystalline form of thecompound of formula (V) with a solvent. In some embodiments, washingcomprises washing the crystalline form of the compound of formula (V)with ethyl acetate.

In certain embodiments, the temperature of the solvent, for example,ethyl acetate, is from about −20° C. to about 10° C., from about −10° C.to about 10° C., from about 0° C. to about 10° C., from about −20° C. toabout 0° C., from about −20° C. to about −10° C., or from about −10° C.to about 0° C. In some embodiments, the temperature of the solvent isfrom about −10° C. to about 10° C.

In certain embodiments, the temperature of the solvent, for example,ethyl acetate, is about −20° C., about −15° C., about −10° C., about −5°C., about 0° C., about 5° C., or about 10° C. In some embodiments, thetemperature of the solvent is about 0° C.

In various embodiments, crystallizing the compound of formula (V) from amixture comprising the compound of formula (V), ethyl acetate and watercomprises:

-   -   (1) cooling the mixture from a first temperature (T¹) to a        second temperature (T²), wherein T¹ is about 50° C., T² is about        22° C., and the mixture is cooled from T¹ to T² at a rate of        about 11° C./hour;    -   (2) holding the compound of formula (V) at T² for at least 6        hours;    -   (3) cooling the compound of formula (V) from T² to a third        temperature (T³), wherein T³ is about 0° C. and the mixture is        cooled from T² to T³ at a rate of about 11° C./hour; and    -   (4) holding the compound of formula (V) at T³ for at least 6        hours,    -   thereby producing a crystalline form of the compound of formula        (V).

It should be understood that the conditions (e.g., temperatures), times,seeding, amounts, compounds, and other parameters and/or variables forcrystallizing the compound of formula (V) as described herein can beequally applicable to the immediately above-described crystallizingprocess, unless otherwise stated or understood from the context (e.g.,the conditions or parameters fall outside the values or ranges in theimmediately above-described crystallizing process).

In certain embodiments, the crystalline form of the compound of formula(V) produced by any of the crystallization methods described herein maybe a crystalline form of the compound of formula (V) as characterizedherein, for example, by an X-ray powder diffraction pattern or peak(s),and/or other characteristic properties of the crystalline form ofbempedoic acid.

In certain embodiments, the purity of the crystalline form of thecompound of formula (V) produced by any of the crystallization methodsdescribed herein is greater than about 85%, greater than about 90%,greater than about 95%, greater than about 96%, greater than about 97%,greater than about 98%, greater than about 99%, greater than about99.1%, greater than about 99.2%, greater than about 99.3%, greater thanabout 99.4%, greater than about 99.5%, greater than about 99.6%, greaterthan about 99.7%, greater than about 99.8%, greater than about 99.85%,greater than about 99.9%, greater than about 99.95%, or greater thanabout 99.98% by weight of the total weight of the crystalline form ofthe compound of formula (V).

Recrystallization of the Crystalline Form of the Compound of Formula (V)

In various embodiments, in step (e), purifying the compound of formula(V) comprises one or more recrystallizations of the crystalline form ofthe compound of formula (V) to provide a pharmaceutical materialcomprising a purified amount of the compound of formula (V).

In certain embodiments, the one or more recrystallizations of thecrystalline form of the compound of formula (V) comprises:

-   -   (1) dissolving the crystalline compound of formula (V) in one or        more solvents, thereby forming a mixture;    -   (2) cooling the mixture from a first temperature (T¹) to a        second temperature (T²), wherein T¹ is from about 40° C. to        about 65° C., T² is from about 20° C. to about 40° C., and the        mixture is cooled from T¹ to T² at a rate of from about 3°        C./hour to about 11° C./hour;    -   (3) holding the mixture at T² for at least 0.5 hours;    -   (4) heating the mixture from T² to a third temperature (T³),        wherein T³ is from about 30° C. to about 50° C., and the mixture        is heated from T² to T³ at a rate of from about 3° C./hour to        about 11° C./hour;    -   (5) holding the mixture at T³ for at least 0.5 hours;    -   (6) cooling the mixture from T³ to a fourth temperature (T⁴),        wherein T⁴ is from about 25° C. to about 40° C. and the mixture        is cooled from T³ to T⁴ at a rate of from about 3° C./hour to        about 11° C./hour;    -   (7) holding the mixture at T⁴ for at least 0.5 hours;    -   (8) cooling the mixture from T⁴ to a fifth temperature (T⁵),        wherein T⁵ is from about −10° C. to about 10° C. and the mixture        is cooled from T⁴ to T⁵ at a rate of from about 3° C./hour to        about 11° C./hour; and    -   (9) holding the mixture at T⁵ for at least 0.5 hours, thereby        producing a pharmaceutical material comprising a purified amount        of crystalline form of the compound of formula (V).

In certain embodiments, in recrystallization step (1), the one or moresolvents comprises ethyl acetate and water. In certain embodiments, theone or more solvents are ethyl acetate and water.

In certain embodiments, in recrystallization step (1), the amount ofethyl acetate in the mixture is from about 2.5 kg/kg to about 3.3 kg/kg,from about 2.7 kg/kg to about 3.3 kg/kg, from about 2.9 kg/kg to about3.3 kg/kg, from about 3.1 kg/kg to about 3.3 kg/kg, from about 2.5 kg/kgto about 3.1 kg/kg, from about 2.5 kg/kg to about 2.9 kg/kg, from about2.5 kg/kg to about 2.7 kg/kg, from about 2.7 kg/kg to about 3.1 kg/kg,from about 2.7 kg/kg to about 2.9 kg/kg, or from about 2.9 kg/kg toabout 3.1 kg/kg, based on the weight of ethyl acetate per kilogram ofthe crystalline compound of formula (V). In some embodiments, inrecrystallization step (1), the amount of ethyl acetate in the mixtureis from about 2.5 kg/kg to about 3.3 kg/kg, based on the weight of ethylacetate per kilogram of the crystalline compound of formula (V). In someembodiments, in recrystallization step (1), the amount of ethyl acetatein the mixture is from about 2.7 kg/kg to about 3.1 kg/kg, based on theweight of ethyl acetate per kilogram of the crystalline compound offormula (V).

In certain embodiments, in recrystallization step (1), the amount ofethyl acetate in the mixture is about 2.5 kg/kg, about 2.7 kg/kg, about2.9 kg/kg, about 3.1 kg/kg, or about 3.3 kg/kg, based on the weight ofethyl acetate per kilogram of the crystalline compound of formula (V).In some embodiments, in recrystallization step (1), the amount of ethylacetate in the mixture is about 2.9 kg/kg, based on the weight of ethylacetate per kilogram of the crystalline compound of formula (V).

In certain embodiments, in recrystallization step (2), T¹ is from about40° C. to about 65° C., from about 45° C. to about 65° C., from about50° C. to about 65° C., from about 55° C. to about 65° C., from about60° C. to about 65° C., from about 40° C. to about 60° C., from about40° C. to about 55° C., from about 40° C. to about 50° C., from about40° C. to about 45° C., from about 45° C. to about 60° C., from about45° C. to about 55° C., from about 45° C. to about 50° C., from about50° C. to about 60° C., from about 50° C. to about 55° C., or from about55° C. to about 60° C. In some embodiments, in recrystallization step(2), T¹ is from about 40° C. to about 65° C. In some embodiments, inrecrystallization step (2), T¹ is from about 50° C. to about 60° C.

In certain embodiments, in recrystallization step (2), T¹ is about 40°C., about 45° C., about 50° C., about 55° C., about 60° C., or about 65°C. In some embodiments, in recrystallization step (2), T¹ is about 55°C.

In certain embodiments, in recrystallization step (2), T² is from about20° C. to about 40° C., from about 25° C. to about 40° C., from about30° C. to about 40° C., from about 35° C. to about 40° C., from about20° C. to about 35° C., from about 20° C. to about 30° C., from about20° C. to about 25° C., from about 25° C. to about 35° C., from about25° C. to about 30° C., or from about 30° C. to about 40° C. In certainembodiments, in recrystallization step (2), T² is from about 25° C. toabout 35° C.

In certain embodiments, in recrystallization step (2), T¹ is about 20°C., about 25° C., about 30° C., about 35° C., or about 40° C. In someembodiments, in recrystallization step (2), T¹ is about 30° C.

In certain embodiments, in recrystallization step (2), the mixture iscooled from T¹ to T² at a rate of from about 3° C./hour to about 11°C./hour, from about 5° C./hour to about 11° C./hour, from about 7°C./hour to about 11° C./hour, from about 9° C./hour to about 11°C./hour, from about 3° C./hour to about 9° C./hour, from about 3°C./hour to about 7° C./hour, from about 3° C./hour to about 5° C./hour,from about 5° C./hour to about 9° C./hour, from about 5° C./hour toabout 7° C./hour, or from about 7° C./hour to about 9° C./hour. In someembodiments, in recrystallization step (2), the mixture is cooled fromT¹ to T² at a rate of from about 3° C./hour to about 11° C./hour. Insome embodiments, in recrystallization step (2), the mixture is cooledfrom T¹ to T² at a rate of from about 5° C./hour to about 7° C./hour.

In certain embodiments, in recrystallization step (2), the mixture iscooled from T¹ to T² at a rate of about 3° C./hour, about 4° C./hour,about 5° C./hour, about 6° C./hour, about 7° C./hour, about 8° C./hour,about 9° C./hour, about 10° C./hour, or about 11° C./hour. In someembodiments, in recrystallization step (2), the mixture is cooled fromT¹ to T² at a rate of about 5° C./hour, about 6° C./hour, or about 7°C./hour.

In certain embodiments, in recrystallization step (3), the mixture isheld at T² for at least 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours,3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours,at least 7 hours, at least 7.5 hours, at least 8 hours, at least 8.5hours, at least 9 hours, at least 9.5 hours, or at least 10 hours. Insome embodiments, in recrystallization step (3), the mixture is held atT² for at least 2 hours.

In certain embodiments, in recrystallization step (3), the mixture isheld at T² for no greater than 1 hour, no greater than 1.5 hours, nogreater than 2 hours, no greater than 2.5 hours, no greater than 3hours, no greater than 3.5 hours, no greater than 4 hours, no greaterthan 4.5 hours, no greater than 5 hours, no greater than 5.5 hours, nogreater than 6 hours, no greater than 6.5 hours, no greater than 7hours, no greater than 7.5 hours, no greater than 8 hours, no greaterthan 8.5 hours, no greater than 9 hours, no greater than 9.5 hours, nogreater than 10 hours, no greater than 10.5 hours, no greater than 11hours, no greater than 11.5 hours, no greater than 12 hours, no greaterthan 16 hours, no greater than 20 hours, or no greater than 24 hours. Insome embodiments, in recrystallization step (3), the mixture is held atT² for no greater than 2 hours.

In certain embodiments, in recrystallization step (4), T³ is from about30° C. to about 50° C., from about 35° C. to about 50° C., from about40° C. to about 50° C., from about 45° C. to about 50° C., from about30° C. to about 45° C., from about 30° C. to about 40° C., from about30° C. to about 35° C., from about 35° C. to about 45° C., from about35° C. to about 40° C., or from about 40° C. to about 45° C. In someembodiments, in recrystallization step (4), T³ is from about 30° C. toabout 50° C. In some embodiments, in recrystallization step (4), T³ isfrom about 35° C. to about 45° C.

In certain embodiments, in recrystallization step (4), T³ is about 30°C., about 35° C., about 40° C., about 45° C., or about 50° C. In someembodiments, in recrystallization step (4), T³ is about 40° C.

In certain embodiments, in recrystallization step (4), the mixture isheated from T² to T³ at a rate of from about 3° C./hour to about 11°C./hour, from about 5° C./hour to about 11° C./hour, from about 7°C./hour to about 11° C./hour, from about 9° C./hour to about 11°C./hour, from about 3° C./hour to about 9° C./hour, from about 3°C./hour to about 7° C./hour, from about 3° C./hour to about 5° C./hour,from about 5° C./hour to about 9° C./hour, from about 5° C./hour toabout 7° C./hour, or from about 7° C./hour to about 9° C./hour. In someembodiments, in recrystallization step (4), the mixture is heated fromT² to T³ at a rate of from about 3° C./hour to about 11° C./hour. Insome embodiments, in recrystallization step (4), the mixture is heatedfrom T² to T³ at a rate of from about 5° C./hour to about 7° C./hour.

In certain embodiments, in recrystallization step (4), the mixture isheated from T² to T³ at a rate of about 3° C./hour, about 4° C./hour,about 5° C./hour, about 6° C./hour, about 7° C./hour, about 8° C./hour,about 9° C./hour, about 10° C./hour, or about 11° C./hour. In someembodiments, in recrystallization step (4), the mixture is heated fromT² to T³ at a rate of about 5° C./hour, about 6° C./hour, or about 7°C./hour.

In certain embodiments, in recrystallization step (5), the mixture isheld at T³ for at least 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours,3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours,at least 7 hours, at least 7.5 hours, at least 8 hours, at least 8.5hours, at least 9 hours, at least 9.5 hours, or at least 10 hours. Insome embodiments, in recrystallization step (5), the mixture is held atT³ for at least 1 hour.

In certain embodiments, in recrystallization step (5), the mixture isheld at T³ for no greater than 1 hour, no greater than 1.5 hours, nogreater than 2 hours, no greater than 2.5 hours, no greater than 3hours, no greater than 3.5 hours, no greater than 4 hours, no greaterthan 4.5 hours, no greater than 5 hours, no greater than 5.5 hours, nogreater than 6 hours, no greater than 6.5 hours, no greater than 7hours, no greater than 7.5 hours, no greater than 8 hours, no greaterthan 8.5 hours, no greater than 9 hours, no greater than 9.5 hours, nogreater than 10 hours, no greater than 10.5 hours, no greater than 11hours, no greater than 11.5 hours, no greater than 12 hours, no greaterthan 16 hours, no greater than 20 hours, or no greater than 24 hours.

In certain embodiments, in recrystallization step (6), T⁴ is from about25° C. to about 40° C., from about 30° C. to about 40° C., from about35° C. to about 40° C., from about 25° C. to about 35° C., from about25° C. to about 30° C., or from about 30° C. to about 35° C. In someembodiments, in recrystallization step (6), T⁴ is from about 25° C. toabout 40° C. In some embodiments, in recrystallization step (6), T⁴ isfrom about 30° C. to about 40° C.

In certain embodiments, in recrystallization step (6), T⁴ is about 25°C., about 30° C., about 35° C., or about 40° C. In some embodiments, inrecrystallization step (6), T⁴ is about 35° C.

In certain embodiments, in recrystallization step (6), the mixture iscooled from T³ to T⁴ at a rate of from about 3° C./hour to about 11°C./hour, from about 5° C./hour to about 11° C./hour, from about 7°C./hour to about 11° C./hour, from about 9° C./hour to about 11°C./hour, from about 3° C./hour to about 9° C./hour, from about 3°C./hour to about 7° C./hour, from about 3° C./hour to about 5° C./hour,from about 5° C./hour to about 9° C./hour, from about 5° C./hour toabout 7° C./hour, or from about 7° C./hour to about 9° C./hour. In someembodiments, in recrystallization step (6), the mixture is cooled fromT³ to T⁴ at a rate of from about 3° C./hour to about 11° C./hour. Insome embodiments, in recrystallization step (6), the mixture is cooledfrom T³ to T⁴ at a rate of from about 5° C./hour to about 7° C./hour.

In certain embodiments, in recrystallization step (6), the mixture iscooled from T³ to T⁴ at a rate of about 3° C./hour, about 4° C./hour,about 5° C./hour, about 6° C./hour, about 7° C./hour, about 8° C./hour,about 9° C./hour, about 10° C./hour, or about 11° C./hour. In someembodiments, in recrystallization step (6), the mixture is cooled fromT³ to T⁴ at a rate of about 5° C./hour, about 6° C./hour, or about 7°C./hour.

In certain embodiments, in recrystallization step (7), the mixture isheld at T⁴ for at least 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours,3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours,at least 7 hours, at least 7.5 hours, at least 8 hours, at least 8.5hours, at least 9 hours, at least 9.5 hours, or at least 10 hours. Insome embodiments, in recrystallization step (7), the mixture is held atT⁴ for at least 2 hours.

In certain embodiments, in recrystallization step (7), the mixture isheld at T⁴ for no greater than 1 hour, no greater than 1.5 hours, nogreater than 2 hours, no greater than 2.5 hours, no greater than 3hours, no greater than 3.5 hours, no greater than 4 hours, no greaterthan 4.5 hours, no greater than 5 hours, no greater than 5.5 hours, nogreater than 6 hours, no greater than 6.5 hours, no greater than 7hours, no greater than 7.5 hours, no greater than 8 hours, no greaterthan 8.5 hours, no greater than 9 hours, no greater than 9.5 hours, nogreater than 10 hours, no greater than 10.5 hours, no greater than 11hours, no greater than 11.5 hours, no greater than 12 hours, no greaterthan 16 hours, no greater than 20 hours, or no greater than 24 hours.

In certain embodiments, in recrystallization step (8), T⁵ is from about−10° C. to about 10° C., from about −5° C. to about 10° C., from about0° C. to about 10° C., from about 5° C. to about 10° C., from about −10°C. to about 5° C., from about −10° C. to about 0° C., from about −10° C.to about −5° C., from about −5° C. to about 5° C., from about −5° C. toabout 0° C., or from about 0° C. to about 5° C. In some embodiments, inrecrystallization step (8), T⁵ is from about −10° C. to about 10° C. Insome embodiments, in recrystallization step (8), T⁵ is from about 0° C.to about 10° C.

In certain embodiments, in recrystallization step (8), T⁵ is about −10°C., about −5° C., about 0° C., about 5° C., or about 10° C. In someembodiments, in recrystallization step (8), T⁵ is about 5° C.

In certain embodiments, in recrystallization step (8), the mixture iscooled from T⁴ to T⁵ at a rate of from about 3° C./hour to about 11°C./hour, from about 5° C./hour to about 11° C./hour, from about 7°C./hour to about 11° C./hour, from about 9° C./hour to about 11°C./hour, from about 3° C./hour to about 9° C./hour, from about 3°C./hour to about 7° C./hour, from about 3° C./hour to about 5° C./hour,from about 5° C./hour to about 9° C./hour, from about 5° C./hour toabout 7° C./hour, or from about 7° C./hour to about 9° C./hour. In someembodiments, in recrystallization step (8), the mixture is cooled fromT⁴ to T⁵ at a rate of from about 3° C./hour to about 11° C./hour. Insome embodiments, in recrystallization step (8), the mixture is cooledfrom T⁴ to T⁵ at a rate of from about 5° C./hour to about 7° C./hour.

In certain embodiments, in recrystallization step (8), the mixture iscooled from T⁴ to T⁵ at a rate of about 3° C./hour, about 4° C./hour,about 5° C./hour, about 6° C./hour, about 7° C./hour, about 8° C./hour,about 9° C./hour, about 10° C./hour, or about 11° C./hour. In someembodiments, in recrystallization step (8), the mixture is cooled fromT⁴ to T⁵ at a rate of about 5° C./hour, about 6° C./hour, or about 7°C./hour.

In certain embodiments, in recrystallization step (9), the mixture isheld at T⁵ for at least 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours,3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours,at least 7 hours, at least 7.5 hours, at least 8 hours, at least 8.5hours, at least 9 hours, at least 9.5 hours, or at least 10 hours. Insome embodiments, in recrystallization step (9), the mixture is held atT⁵ for at least 4 hours.

In certain embodiments, in recrystallization step (9), the mixture isheld at T⁵ for no greater than 1 hour, no greater than 1.5 hours, nogreater than 2 hours, no greater than 2.5 hours, no greater than 3hours, no greater than 3.5 hours, no greater than 4 hours, no greaterthan 4.5 hours, no greater than 5 hours, no greater than 5.5 hours, nogreater than 6 hours, no greater than 6.5 hours, no greater than 7hours, no greater than 7.5 hours, no greater than 8 hours, no greaterthan 8.5 hours, no greater than 9 hours, no greater than 9.5 hours, nogreater than 10 hours, no greater than 10.5 hours, no greater than 11hours, no greater than 11.5 hours, no greater than 12 hours, no greaterthan 16 hours, no greater than 20 hours, or no greater than 24 hours.

In certain embodiments, recrystallizing the compound of formula (V)further comprises seeding the mixture with an amount of a crystallineform of the compound of formula (V) prior to recrystallization step (2),during recrystallization step (2), during recrystallization step (3),during recrystallization step (4), during recrystallization step (5),during recrystallization step (6), during recrystallization step (7),during recrystallization step (8), during recrystallization step (9), orany combination thereof, in order to facilitate the crystallization ofthe compound of formula (V).

It should be understood that the conditions (e.g., temperatures), times,seeding, amounts, compounds, and other parameter and/or variables forcrystallizing the compound of formula (V) as described herein can beequally applicable to recrystallization of the compound of formula (V),unless otherwise stated or understood from the context, or as notedbelow.

For example, in certain embodiments, recrystallizing the compound offormula (V) comprises filtration of the crystalline form of the compoundof formula (V). In certain embodiments, filtering the crystalline formof the compound of formula (V) occurs at a temperature of from about−20° C. to about 15° C., from about −15° C. to about 15° C., from about−10° C. to about 15° C., from about −5° C. to about 15° C., from about0° C. to about 15° C., from about 5° C. to about 15° C., from about 10°C. to about 15° C., from about −20° C. to about 10° C., from about −20°C. to about 5° C., from about −20° C. to about 0° C., from about −20° C.to about −5° C., from about −20° C. to about −10° C., from about −20° C.to about −15° C., from about −15° C. to about 10° C., from about −15° C.to about 5° C., from about −15° C. to about 0° C., from about −15° C. toabout −5° C., from about −15° C. to about −10° C., from about −10° C. toabout 10° C., from about −10° C. to about 5° C., from about −10° C. toabout 0° C., from about −10° C. to about −5° C., from about −5° C. toabout 10° C., from about −5° C. to about 5° C., from about −5° C. toabout 0° C., from about 0° C. to about 10° C., from about 0° C. to about5° C., or from about 5° C. to about 10° C. In some embodiments,filtering of the crystalline form of the compound of formula (V) occursat a temperature of from about 0° C. to about 15° C.

In certain embodiments, filtering of the crystalline form of thecompound of formula (V) occurs at a temperature of about −20° C., about−15° C., about −10° C., about −5° C., about 0° C., about 5° C., about10° C., or about 15° C. In some embodiments, filtering of thecrystalline form of the compound of formula (V) occurs at a temperatureof about 0° C., about 5° C., about 10° C., or about 15° C.

In certain embodiments, filtration further comprises washing. In certainembodiments, washing comprises washing the crystalline form of thecompound of formula (V) with a solvent. In some embodiments, washingcomprises washing the crystalline form of the compound of formula (V)with acetonitrile.

In certain embodiments, recrystallizing the compound of formula (V)comprises isolating the crystalline form of the compound of formula (V)from the mixture by centrifugation.

In certain embodiments, isolation of the crystalline form of thecompound of formula (V) by centrifugation further comprises washing. Incertain embodiments, washing comprises washing the crystalline form ofthe compound of formula (V) with a solvent. In some embodiments, washingcomprises washing the crystalline form of the compound of formula (V)with acetonitrile.

In certain embodiments, the temperature of the solvent, for example,acetonitrile, is from about −20° C. to about 30° C., from about −10° C.to about 30° C., from about 0° C. to about 30° C., from about 10° C. toabout 30° C., from about −20° C. to about 20° C., from about −20° C. toabout 10° C., from about −20° C. to about 0° C., from about −20° C. toabout −10° C., from about −10° C. to about 20° C., from about −10° C. toabout 10° C., from about −10° C. to about 0° C., from about 0° C. toabout 20° C., from about 0° C. to about 10° C., or from about 10° C. toabout 20° C. In some embodiments, the temperature of the solvent is fromabout 10° C. to about 30° C.

In certain embodiments, the temperature of the solvent, for example,acetonitrile, is about −20° C., about −10° C., about 0° C., about 10°C., about 20° C., or about 30° C. In some embodiments, the temperatureof the solvent is about 20° C.

In certain embodiments, recrystallizing the compound of formula (V)comprises drying.

In certain embodiments, drying comprises heating the crystalline form ofthe compound of formula (V) to a temperature of less than about 85° C.,less than about 75° C., less than about 65° C., less than about 55° C.,less than about 45° C., less than about 35° C., or less than about 25°C. In some embodiments, the drying step comprises heating thecrystalline form of the compound of formula (V) to a temperature of lessthan about 85° C. In some embodiments, the drying step comprises heatingthe crystalline form of the compound of formula (V) to a temperature ofless than about 45° C.

In certain embodiments, the one or more recrystallizations of thecrystalline form of the compound of formula (V) comprises 1, 2, 3, 4, 5,6, 7, 8, 9 or 10 recrystallizations.

In certain embodiments, the one or more recrystallizations of thecrystalline form of the compound of formula (V) comprises:

-   -   (1) dissolving the crystalline compound of formula (V) in one or        more solvents comprising ethyl acetate and water, thereby        forming a mixture;    -   (2) cooling the mixture from a first temperature (T¹) to a        second temperature (T²), wherein T¹ is about 55° C., T² is about        30° C., and the mixture is cooled from T¹ to T² at a rate of        from about 5° C./hour to about 7° C./hour;    -   (3) holding the compound of formula (V) at T² for at least 2        hours;    -   (4) heating the mixture from T² to a third temperature (T³),        wherein T³ is about 40° C. and the mixture is heated from T² to        T³ at a rate of from about 5° C./hour to about 7° C./hour;    -   (5) holding the mixture at T³ for at least 1 hour;    -   (6) cooling the mixture from T³ to a fourth temperature (T⁴),        wherein T⁴ is about 35° C. and the mixture is cooled from T³ to        T⁴ at a rate of from about 5° C./hour to about 7° C./hour;    -   (7) holding the mixture at T⁴ for at least 2 hours;    -   (8) cooling the mixture from T⁴ to a fifth temperature (T⁵),        wherein T⁵ is about 5° C. and the mixture is cooled from T⁴ to        T⁵ at a rate of from about 5° C./hour to about 7° C./hour; and    -   (9) holding the mixture at T⁵ for at least 4 hours, thereby        producing a pharmaceutical material comprising a purified amount        of crystalline form of the compound of formula (V).

It should be understood that the conditions (e.g., temperatures), times,seeding, amounts, compounds, and other parameters and/or variables forcrystallizing and/or recrystallizing the compound of formula (V) asdescribed herein can be equally applicable to the immediatelyabove-described recrystallizing process, unless otherwise stated orunderstood from the context (e.g., the conditions or parameters falloutside the values or ranges in the immediately above-describedrecrystallizing process).

In certain embodiments, the crystalline form of the compound of formula(V) in the pharmaceutical material produced by any of therecrystallization methods described herein may be a crystalline form ofthe compound of formula (V) as characterized herein, for example, by anX-ray powder diffraction pattern or peak(s), and/or other characteristicproperties of the crystalline form of bempedoic acid.

In various embodiments, the purified amount of the compound of formula(V) in the pharmaceutical material is greater than 99.0%, greater thanabout 99.1%, greater than about 99.2%, greater than about 99.3%, greaterthan about 99.4%, greater than about 99.5%, greater than about 99.6%,greater than about 99.7%, greater than about 99.8%, greater than about99.85%, greater than about 99.9%, greater than about 99.95%, or greaterthan about 99.98% by weight of the total weight of the pharmaceuticalmaterial. In some embodiments, the purified amount of the compound offormula (V) in the pharmaceutical material is greater than 99.0% byweight of the total weight of the pharmaceutical material. In someembodiments, the purified amount of the compound of formula (V) in thepharmaceutical material is greater than about 99.5% by weight of thetotal weight of the pharmaceutical material. In some embodiments, thepurified amount of the compound of formula (V) in the pharmaceuticalmaterial is greater than about 99.7% by weight of the total weight ofthe pharmaceutical material. In some embodiments, the purified amount ofthe compound of formula (V) in the pharmaceutical material is greaterthan about 99.85% by weight of the total weight of the pharmaceuticalmaterial.

In certain embodiments, subsequent to recrystallizing the crystallineform of the compound of formula (V), which provides a recrystallizedcompound of formula (V), the method comprises contacting therecrystallized compound of formula (V) with charcoal, and filtering thecharcoal to provide a pharmaceutical material comprising a purifiedamount of the compound of formula (V). In some embodiments, contactingthe compound of formula (V) with charcoal comprises contacting thecompound of formula (V) with a solution, wherein the solution comprisesacetonitrile and activated charcoal (e.g., 5% (w/w) activated charcoal).

In certain embodiments, the methods described herein can be used toprepare a batch of bempedoic acid. In certain embodiments, the methodsdescribed herein can be used to prepare a batch of a pharmaceuticalmaterial, wherein the pharmaceutical material comprises a purifiedamount of the compound of formula (V). In certain embodiments, thepurified amount of the compound of formula (V), or a pharmaceuticallyacceptable salt thereof, is greater than 99.0% by weight of the totalweight of the pharmaceutical material.

In certain embodiments, the batch is in an amount of about 1 kg, 2 kg, 3kg, 4 kg, 5 kg, 10 kg, 20 kg, 30 kg, 40 kg, 50 kg, 60 kg, 70 kg, 80 kg,90 kg, 100 kg, 200 kg, 300 kg, 400 kg, 500 kg, 600 kg, 700 kg, 800 kg,900 kg, or 1000 kg.

IV. High Purity Compositions of Bempedoic Acid

As described herein, in one aspect, the invention providespharmaceutical materials comprising bempedoic acid such as a crystallineform of bempedoic acid, or a pharmaceutically acceptable salt thereof.

In various embodiments, a pharmaceutical material generally comprises acrystalline form of the compound of formula (V):

or a pharmaceutically acceptable salt thereof, wherein thepharmaceutical material comprises the compound of formula (V), or apharmaceutically acceptable salt thereof, in an amount greater than99.0% by weight based on the total weight of the pharmaceuticalmaterial. In some embodiments, the amount of the compound of formula (V)in the pharmaceutical material is greater than about 99.1%, greater thanabout 99.2%, greater than about 99.3%, greater than about 99.4%, greaterthan about 99.5%, greater than about 99.6%, greater than about 99.7%,greater than about 99.8%, greater than about 99.85%, greater than about99.9%, greater than about 99.95%, or greater than about 99.98% by weightof the total weight of the pharmaceutical material. In some embodiments,the pharmaceutical material comprises the compound of formula (V) in anamount greater than 99.5% by weight based on the total weight of thepharmaceutical material. In some embodiments, the pharmaceuticalmaterial comprises the compound of formula (V) in an amount greater than99.7% by weight based on the total weight of the pharmaceuticalmaterial. In some embodiments, the pharmaceutical material comprises thecompound of formula (V) in an amount greater than 99.9% by weight basedon the total weight of the pharmaceutical material.

In certain embodiments, the pharmaceutical material comprises thecompound of formula (V) in an amount of from about 98% to about 102% byweight based on the total weight of the pharmaceutical material(anhydrous, solvent-free basis), as determined by a high performanceliquid chromatography (HPLC) assay.

In certain embodiments, the HPLC assay comprises one or more of:

-   -   (i) a Waters XBridge BEH C18 column (4.6 mm i.d.×150 mm, 2.5        μm);    -   (ii) a column temperature of about 40° C.;    -   (iii) a mobile phase comprising about 0.05% phosphoric acid in        water/acetonitrile (about 50:50);    -   (iv) isocratic elution;    -   (v) a flow rate of about 1.2 mL/minute;    -   (vi) a sample temperature of ambient temperature;    -   (vii) detection at 215 nm; and    -   (viii) the retention time of the compound of formula (V) is        about 4.6 minutes.

In some embodiments, the HPLC assay comprises each of the above, i.e.,(i)-(viii).

In certain embodiments, the crystalline form of the compound of formula(V) may be a crystalline form of the compound of formula (V) ascharacterized herein, for example, by an X-ray powder diffractionpattern or peak(s), and/or other characteristic properties of thecrystalline form of bempedoic acid.

In certain embodiments, a pharmaceutical material described herein cancomprise a compound of formula (VI):

or a pharmaceutically acceptable salt thereof. The compound of formula(VI), or a pharmaceutically acceptable salt thereof, is also referred toherein as the “diol impurity.”

In certain embodiments, the amount of the diol impurity in thepharmaceutical material is less than about 0.15%, about 0.125%, about0.1%, about 0.075%, about 0.05%, about 0.025%, about 0.01%, about0.001%, or about 0.0001% by weight based on the total weight of thepharmaceutical material. In some embodiments, the amount of the diolimpurity in the pharmaceutical material is less than about 1.25% byweight based on the total weight of the pharmaceutical material. In someembodiments, the amount of the diol impurity in the pharmaceuticalmaterial is less than about 0.15% by weight based on the total weight ofthe pharmaceutical material. In some embodiments, the amount of the diolimpurity in the pharmaceutical material is less than about 0.1% byweight based on the total weight of the pharmaceutical material.

In certain embodiments, the pharmaceutical material comprises thecompound of formula (VI), or a pharmaceutically acceptable salt thereof,in an amount no greater than about 0.15%, about 0.125%, about 0.1%,about 0.075%, about 0.05%, about 0.025%, about 0.01%, about 0.001%, orabout 0.0001% by weight based on the total weight of the pharmaceuticalmaterial. In some embodiments, the pharmaceutical material comprises thecompound of formula (VI), or a pharmaceutically acceptable salt thereof,in an amount no greater than about 0.125% by weight based on the totalweight of the pharmaceutical material. In some embodiments, thepharmaceutical material comprises the compound of formula (VI), or apharmaceutically acceptable salt thereof, in an amount no greater thanabout 0.15% by weight based on the total weight of the pharmaceuticalmaterial. In some embodiments, the pharmaceutical material comprises thecompound of formula (VI), or a pharmaceutically acceptable salt thereof,in an amount no greater than about 0.1% by weight based on the totalweight of the pharmaceutical material.

In certain embodiments, the amount of the diol impurity in thepharmaceutical material is from about 0.0001% to about 0.15%, from about0.001% to about 0.15%, from about 0.01% to about 0.15%, from about0.025% to about 0.15%, from about 0.05% to about 0.15%, from about0.075% to about 0.15%, from about 0.1% to about 0.15%, from about 0.125%to about 0.15%, from about 0.01% to about 0.125%, from about 0.01% toabout 0.1%, from about 0.01% to about 0.075%, from about 0.01% to about0.05%, from about 0.01% to about 0.025%, from about 0.025% to about0.125%, from about 0.025% to about 0.1%, from about 0.025% to about0.075%, from about 0.025% to about 0.05%, from about 0.05% to about0.125%, from about 0.05% to about 0.1%, from about 0.05% to about0.075%, from about 0.075% to about 0.125%, from about 0.075% to about0.1%, or from about 0.1% to about 0.125% by weight based on the totalweight of the pharmaceutical material. In some embodiments, the amountof the diol impurity in the pharmaceutical material is from about 0.01%to about 0.15% by weight based on the total weight of the pharmaceuticalmaterial. In some embodiments, the amount of the diol impurity in thepharmaceutical material is from about 0.01% to about 0.1% by weightbased on the total weight of the pharmaceutical material.

In certain embodiments, a pharmaceutical material described herein cancomprise the compound of formula (VII):

or a pharmaceutically acceptable salt thereof. The compound of formula(VII), or a pharmaceutically acceptable salt thereof, is also referredto herein as the “ketone impurity.”

In certain embodiments, the amount of the ketone impurity in thepharmaceutical material is less than about 0.15%, about 0.125%, about0.1%, about 0.075%, about 0.05%, about 0.025%, about 0.01%, about0.001%, or about 0.0001% by weight based on the total weight of thepharmaceutical material. In certain embodiments, the amount of theketone impurity in the pharmaceutical material is less than about 0.15%by weight based on the total weight of the pharmaceutical material. Incertain embodiments, the amount of the ketone impurity in thepharmaceutical material is less than about 0.05% by weight based on thetotal weight of the pharmaceutical material.

In certain embodiments, the pharmaceutical material comprises thecompound of formula (VII), or a pharmaceutically acceptable saltthereof, in an amount no greater than about 0.15%, about 0.125%, about0.1%, about 0.075%, about 0.05%, about 0.025%, about 0.01%, about0.001%, or about 0.0001% by weight based on the total weight of thepharmaceutical material. In some embodiments, the pharmaceuticalmaterial comprises the compound of formula (VII), or a pharmaceuticallyacceptable salt thereof, in an amount no greater than about 0.15% byweight based on the total weight of the pharmaceutical material. In someembodiments, the pharmaceutical material comprises the compound offormula (VII), or a pharmaceutically acceptable salt thereof, in anamount no greater than about 0.05% by weight based on the total weightof the pharmaceutical material.

In certain embodiments, the amount of the ketone impurity in thepharmaceutical material is from about 0.0001% to about 0.15%, from about0.001% to about 0.15%, from about 0.01% to about 0.15%, from about0.025% to about 0.15%, from about 0.05% to about 0.15%, from about0.075% to about 0.15%, from about 0.1% to about 0.15%, from about 0.125%to about 0.15%, from about 0.01% to about 0.125%, from about 0.01% toabout 0.1%, from about 0.01% to about 0.075%, from about 0.01% to about0.05%, from about 0.01% to about 0.025%, from about 0.025% to about0.125%, from about 0.025% to about 0.1%, from about 0.025% to about0.075%, from about 0.025% to about 0.05%, from about 0.05% to about0.125%, from about 0.05% to about 0.1%, from about 0.05% to about0.075%, from about 0.075% to about 0.125%, from about 0.075% to about0.1%, or from about 0.1% to about 0.125% by weight based on the totalweight of the pharmaceutical material. In some embodiments, the amountof the ketone impurity in the pharmaceutical material is from about0.01% to about 0.15% by weight based on the total weight of thepharmaceutical material. In some embodiments, the amount of the ketoneimpurity in the pharmaceutical material is from about 0.01% to about0.05% by weight based on the total weight of the pharmaceuticalmaterial.

In certain embodiments, a pharmaceutical material described herein cancomprise the compound of formula (VIII):

or a pharmaceutically acceptable salt thereof. The compound of formula(VIII), or a pharmaceutically acceptable salt thereof, is also referredto herein as the “acetate impurity.”

In certain embodiments, the amount of the acetate impurity in thepharmaceutical material is less than about 0.15%, about 0.125%, about0.1%, about 0.075%, about 0.05%, about 0.025%, about 0.01%, about 0.001%or about 0.0001% by weight based on the total weight of thepharmaceutical material.

In certain embodiments, the pharmaceutical material comprises thecompound of formula (VIII), or a pharmaceutically acceptable saltthereof, in an amount no greater than about 0.15%, about 0.125%, about0.1%, about 0.075%, about 0.05%, about 0.025%, about 0.01%, about0.001%, or about 0.0001% by weight based on the total weight of thepharmaceutical material.

In certain embodiments, the amount of the acetate impurity in thepharmaceutical material is from about 0.0001% to about 0.15%, from about0.001% to about 0.15%, from about 0.01% to about 0.15%, from about0.025% to about 0.15%, from about 0.05% to about 0.15%, from about0.075% to about 0.15%, from about 0.1% to about 0.15%, from about 0.125%to about 0.15%, from about 0.01% to about 0.125%, from about 0.01% toabout 0.1%, from about 0.01% to about 0.075%, from about 0.01% to about0.05%, from about 0.01% to about 0.025%, from about 0.025% to about0.125%, from about 0.025% to about 0.1%, from about 0.025% to about0.075%, from about 0.025% to about 0.05%, from about 0.05% to about0.125%, from about 0.05% to about 0.1%, from about 0.05% to about0.075%, from about 0.075% to about 0.125%, from about 0.075% to about0.1%, or from about 0.1% to about 0.125% by weight based on the totalweight of the pharmaceutical material.

In certain embodiments, a pharmaceutical material described herein cancomprise the compound of formula (IX):

or a pharmaceutically acceptable salt thereof. The compound of formula(IX), or a pharmaceutically acceptable salt thereof, is also referred toherein as the “dimer impurity.”

In certain embodiments, the amount of the dimer impurity in thepharmaceutical material is less than about 0.15%, about 0.125%, about0.1%, about 0.075%, about 0.05%, about 0.025%, about 0.01%, about 0.001%or about 0.0001% by weight based on the total weight of thepharmaceutical material.

In certain embodiments, the pharmaceutical material comprises thecompound of formula (IX), or a pharmaceutically acceptable salt thereof,in an amount no greater than about 0.15%, about 0.125%, about 0.1%,about 0.075%, about 0.05%, about 0.025%, about 0.01%, about 0.001%, orabout 0.0001% by weight based on the total weight of the pharmaceuticalmaterial.

In certain embodiments, the amount of the dimer impurity in thepharmaceutical material is from about 0.0001% to about 0.15%, from about0.0005% to about 0.15%, from about 0.01% to about 0.15%, from about0.025% to about 0.15%, from about 0.05% to about 0.15%, from about0.075% to about 0.15%, from about 0.1% to about 0.15%, from about 0.125%to about 0.15%, from about 0.01% to about 0.125%, from about 0.01% toabout 0.1%, from about 0.01% to about 0.075%, from about 0.01% to about0.05%, from about 0.01% to about 0.025%, from about 0.025% to about0.125%, from about 0.025% to about 0.1%, from about 0.025% to about0.075%, from about 0.025% to about 0.05%, from about 0.05% to about0.125%, from about 0.05% to about 0.1%, from about 0.05% to about0.075%, from about 0.075% to about 0.125%, from about 0.075% to about0.1%, or from about 0.1% to about 0.125% by weight based on the totalweight of the pharmaceutical material.

In certain embodiments, a pharmaceutical material described herein cancomprise the compound of formula (X):

or a pharmaceutically acceptable salt thereof. The compound of formula(X), or a pharmaceutically acceptable salt thereof, is also referred toherein as the “monoethyl ester impurity.”

In certain embodiments, the amount of the monoethyl ester impurity inthe pharmaceutical material is less than about 0.15%, about 0.125%,about 0.1%, about 0.075%, about 0.05%, about 0.025%, about 0.01%, about0.001% or about 0.0001% by weight based on the total weight of thepharmaceutical material.

In certain embodiments, the pharmaceutical material comprises thecompound of formula (X), or a pharmaceutically acceptable salt thereof,in an amount no greater than about 0.15%, about 0.125%, about 0.1%,about 0.075%, about 0.05%, about 0.025%, about 0.01%, about 0.001%, orabout 0.0001% by weight based on the total weight of the pharmaceuticalmaterial.

In certain embodiments, the amount of the monoethyl ester impurity inthe pharmaceutical material is from about 0.0001% to about 0.15%, fromabout 0.0005% to about 0.15%, from about 0.01% to about 0.15%, fromabout 0.025% to about 0.15%, from about 0.05% to about 0.15%, from about0.075% to about 0.15%, from about 0.1% to about 0.15%, from about 0.125%to about 0.15%, from about 0.01% to about 0.125%, from about 0.01% toabout 0.1%, from about 0.01% to about 0.075%, from about 0.01% to about0.05%, from about 0.01% to about 0.025%, from about 0.025% to about0.125%, from about 0.025% to about 0.1%, from about 0.025% to about0.075%, from about 0.025% to about 0.05%, from about 0.05% to about0.125%, from about 0.05% to about 0.1%, from about 0.05% to about0.075%, from about 0.075% to about 0.125%, from about 0.075% to about0.1%, or from about 0.1% to about 0.125% by weight based on the totalweight of the pharmaceutical material.

In certain embodiments, a pharmaceutical material described herein cancomprise the compound of formula (XI):

or a pharmaceutically acceptable salt thereof. The compound of formula(XI), or a pharmaceutically acceptable salt thereof, is also referred toherein as the “diethyl ester impurity.”

In certain embodiments, the amount of the diethyl ester impurity in thepharmaceutical material is less than about 0.15%, about 0.125%, about0.1%, about 0.075%, about 0.05%, about 0.025%, about 0.01%, about 0.001%or about 0.0001% by weight based on the total weight of thepharmaceutical material.

In certain embodiments, the pharmaceutical material comprises thecompound of formula (XI), or a pharmaceutically acceptable salt thereof,in an amount no greater than about 0.15%, about 0.125%, about 0.1%,about 0.075%, about 0.05%, about 0.025%, about 0.01%, about 0.001%, orabout 0.0001% by weight based on the total weight of the pharmaceuticalmaterial.

In certain embodiments, the amount of the diethyl ester impurity in thepharmaceutical material is from about 0.0001% to about 0.15%, from about0.0005% to about 0.15%, from about 0.01% to about 0.15%, from about0.025% to about 0.15%, from about 0.05% to about 0.15%, from about0.075% to about 0.15%, from about 0.1% to about 0.15%, from about 0.125%to about 0.15%, from about 0.01% to about 0.125%, from about 0.01% toabout 0.1%, from about 0.01% to about 0.075%, from about 0.01% to about0.05%, from about 0.01% to about 0.025%, from about 0.025% to about0.125%, from about 0.025% to about 0.1%, from about 0.025% to about0.075%, from about 0.025% to about 0.05%, from about 0.05% to about0.125%, from about 0.05% to about 0.1%, from about 0.05% to about0.075%, from about 0.075% to about 0.125%, from about 0.075% to about0.1%, or from about 0.1% to about 0.125% by weight based on the totalweight of the pharmaceutical material.

In certain embodiments, a pharmaceutical material described herein cancomprise an impurity with a relative retention time (RRT) of about 1.04to about 1.05, as determined by HPLC. In certain embodiments, apharmaceutical material described herein can comprise an impurity with arelative retention time (RRT) of about 1.06 to about 1.08, as determinedby HPLC. In certain embodiments, a pharmaceutical material describedherein can comprise an impurity with a relative retention time (RRT) ofabout 1.18 to about 1.20, as determined by HPLC. In certain embodiments,a pharmaceutical material described herein can comprise an impurity witha relative retention time (RRT) of about 1.36, as determined by HPLC. Incertain embodiments, a pharmaceutical material described herein cancomprise an impurity with a RRT of about 1.43, as determined by HPLC. Incertain embodiments, a pharmaceutical material described herein cancomprise an impurity with a RRT of about 1.86, as determined by HPLC. Incertain embodiments, a pharmaceutical material described herein cancomprise a first impurity with a RRT of about 1.36 and a second impuritywith a RRT of about 1.86, as determined by HPLC. In certain embodiments,the RRT of the impurity is based on the retention time of bempedoicacid, wherein the RRT of bempedoic acid is about 1.00.

In certain embodiments, a pharmaceutical material described herein cancomprise one or more unidentified impurities (e.g., impurities in thepharmaceutical material whose chemical structure cannot be determinedbut whose RRT is known).

In certain embodiments, the pharmaceutical material comprises one ormore of the impurities described herein, as determined by a highperformance liquid chromatography (HPLC) assay.

In certain embodiments, the HPLC assay comprises one or more of:

-   -   (i) a Waters XBridge BEH C18 column (4.6 mm i.d.×150 mm, 2.5        μm);    -   (ii) a column temperature of about 40° C.;    -   (iii) a first mobile phase comprising about 0.05% formic acid in        water;    -   (iv) a second mobile phase comprising about 0.05% formic acid in        acetonitrile;    -   (v) a flow rate of about 1.2 mL/minute;    -   (vi) a sample temperature of ambient temperature; and    -   (vii) the retention time of the compound of formula (V) is about        15.2 minutes.

In some embodiments, the HPLC assay comprises each of the above, i.e.,(i)-(vii). In certain embodiments, the amount of the one or moreunidentified impurities in the pharmaceutical material is less thanabout 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about0.06%, about 0.07%, about 0.08%, about 0.09%, or about 0.1% by weightbased on the total weight of the pharmaceutical material. In someembodiments, the amount of the one or more unidentified impurities inthe pharmaceutical material is less than about 0.05% by weight based onthe total weight of the pharmaceutical material.

In certain embodiments, the amount of the one or more unidentifiedimpurities in the pharmaceutical material is from about 0.0001% to about0.1%, from about 0.0005% to about 0.1%, from about 0.001% to about 0.1%,from about 0.005% to about 0.1%, from about 0.01% to about 0.1%, fromabout 0.05% to about 0.1%, from about 0.0001% to about 0.05%, from about0.0001% to about 0.01%, from about 0.0001% to about 0.005%, from about0.0001% to about 0.001%, from about 0.0001% to about 0.0005%, from about0.0005% to about 0.05%, from about 0.0005% to about 0.01%, from about0.0005% to about 0.005%, from about 0.0005% to about 0.001%, from about0.001% to about 0.05%, from about 0.001% to about 0.01%, from about0.001% to about 0.005%, from about 0.005% to about 0.05%, from about0.005% to about 0.01%, or from about 0.01% to about 0.05% by weightbased on the total weight of the pharmaceutical material. In certainembodiments, the amount of the one or more unidentified impurities inthe pharmaceutical material is from about 0.0001% to about 0.1% byweight based on the total weight of the pharmaceutical material. Incertain embodiments, the amount of the one or more unidentifiedimpurities in the pharmaceutical material is from about 0.05% to about0.1% by weight based on the total weight of the pharmaceutical material.

V. Pharmaceutical Compositions

In another aspect, provided herein are pharmaceutical compositionscomprising bempedoic acid, or a pharmaceutically acceptable saltthereof, as described and/or made herein, including any of thepharmaceutical materials as well as the impurities. In variousembodiments, a pharmaceutical composition generally comprises apharmaceutical material as described herein; and a pharmaceuticallyacceptable excipient. For example, the pharmaceutical material cancomprise greater than 99.0% of the compound of formula (V), or apharmaceutically acceptable salt thereof.

In certain embodiments, the pharmaceutical compositions may be speciallyformulated for administration as solid or liquid dosage forms. In someembodiments, the pharmaceutical compositions described herein areformulated for administration as an oral dosage form. Examples of oraldosage forms include, but are not limited to a drench, a tablet, acapsule, a cachet, a pill, an emulsion, a lozenge, a solution, asuspension, a bolus, a powder, an elixir or syrup, a pastille, amouthwash, a granule, or a paste for application to the tongue. In someembodiments, the pharmaceutical compositions described herein areformulated as a dosage form suitable for parenteral administration. Insome embodiments, the pharmaceutical compositions described herein areadministered by subcutaneous, intramuscular, intravenous or epiduralinjection. Examples of dosage forms suitable for parenteraladministration include, but are not limited to, a sterile solution orsuspension, or a sustained-release formulation. In some embodiments, thepharmaceutical compositions described herein are formulated as a dosageform suitable for topical application. Examples of dosage forms suitablefor topical administration include, but are not limited to, a powder, aspray, an ointment, a paste, a cream, a lotion, a gel, a solution, apatch, an inhalant, or a controlled-release patch or spray applied tothe skin. In some embodiments, the pharmaceutical compositions describedherein are formulated as a dosage form suitable for intravaginal orintrarectal administration. Examples of dosage forms suitable forintravaginal or intrarectal administration include, but are not limitedto, a pessary, a cream, or a foam. In some embodiments, thepharmaceutical compositions described herein are formulated as a dosageform suitable for sublingual, ocular, transdermal or nasaladministration.

In certain embodiments, the solid dosage forms described herein to beused for oral administration are prepared by mixing a pharmaceuticalmaterial with one or more pharmaceutically acceptable excipients.Pharmaceutical excipients can be selected from the group consisting of afiller or extender, a sweetening agent, a binder, a humectant, adisintegrating agent, a preservative, a perfuming agent, a flavoringagent, an antioxidant, a solution retarding agent, an absorptionaccelerator, a wetting agent, an absorbent, a lubricant, a coloringagent, and a controlled release agent. In some embodiments, when thesolid dosage form is a capsule, a tablet or a pill, the pharmaceuticalcompositions described herein may also comprise a buffering agent. Insome embodiments, when the solid dosage form is a gelatin capsule, thepharmaceutical composition may further comprise one or more excipientsselected from lactose, a milk sugar, a high molecular weightpolyethylene glycol and combinations thereof.

In certain embodiments, a pharmaceutical composition of the inventionmay comprise one or more excipients selected from the group consistingof a cyclodextrin, a cellulose, a liposome, a micelle forming agent, anda polymeric carrier. In some embodiments, the pharmaceuticalcompositions of the present invention comprise an antibacterial agent,an antifungal agent, or combinations thereof. Examples antibacterial andantifungal agents include, but are not limited to, paraben,chlorobutanol, phenol and sorbic acid. In some embodiments, thepharmaceutical compositions of the present invention comprise anisotonic agent

In certain embodiments, the dosage forms of the present invention may beformulated so as to provide slow or controlled release of the compoundof formula (V), or a pharmaceutically acceptable salt thereof. See,e.g., PCT/US2019/018356, which discloses sustained release formulationsof bempedoic acid. In some embodiments, the dosage forms of the presentinvention may be formulated for rapid release.

In certain embodiments, a liquid dosage form of a pharmaceuticalcomposition of the invention comprises one or more of the following; aninert diluent, a solubilizing agent and an emulsifier.

In certain embodiments, oral suspensions of a pharmaceutical compositionof the invention comprise one or more suspending agents including anethoxylated isostearyl alcohol, a polyoxyethylene sorbitol and sorbitanester, a microcrystalline cellulose, an aluminum metahydroxide,bentonite, agar-agar and tragacanth, and mixtures thereof.

In some embodiments, the ointments, pastes, creams and gels of apharmaceutical composition of the invention comprise one or moreexcipients, wherein the one or more excipients can comprise an animalfat, a vegetable fat, an oil, a wax, a paraffin, a starch, a tragacanth,a cellulose derivative, a polyethylene glycol, a silicone, a bentonite,silicic acid, talc, zinc oxide, or mixtures thereof.

In certain embodiments, powders and sprays of a pharmaceuticalcomposition of the invention comprise one or more excipients, whereinthe one or more excipients can comprise lactose, talc, silicic acid,aluminum hydroxide, a calcium silicate, a polyamide powder, or mixturesthereof. In some embodiments, a spray of the present invention cancomprise a customary propellant, wherein the customary propellantcomprises one or more of a chlorofluorohydrocarbon and a volatileunsubstituted hydrocarbon.

In certain embodiments, a transdermal patch of a pharmaceuticalcomposition of the invention provides controlled delivery of thecompound of formula (V), or a pharmaceutically acceptable salt thereof,to the body. In some embodiments, ophthalmic formulations, eyeointments, powders, solutions and the like, are also included within thescope of the present invention.

In certain embodiments, the pharmaceutical compositions described hereinmay be administered in a unit dosage form and may be prepared by anymethod well known in the art of pharmacy. The amount of the compound offormula (V), or a pharmaceutically acceptable salt thereof, present in asingle dosage form may vary depending upon the patient being treatedand/or the particular mode of administration.

In certain embodiments, the amount of the compound of formula (V), or apharmaceutically acceptable salt thereof, that can be combined with apharmaceutically acceptable carrier to produce a single dosage form willgenerally be an amount of the compound of formula (V), or apharmaceutically acceptable salt thereof, that produces a therapeuticeffect.

In various embodiments, bempedoic acid, or a pharmaceutically acceptablesalt thereof, or a pharmaceutical material of the present invention, canbe prepared as a fixed dose formulation (see, e.g., U.S. PatentApplication Publication No. 2018/0338922 and International ApplicationNo. WO 2018/218147).

VI. Methods of Treatment and Administration

In various embodiments, bempedoic acid, or a pharmaceutically acceptablesalt thereof, as described and/or made herein, including apharmaceutical material and/or a pharmaceutical composition, may be usedfor the treatment or prevention of a variety of diseases and disorders.The methods of treating a disease or disorder generally compriseadministering to a patient, in need thereof, a therapeutically effectiveamount of a pharmaceutical material comprising a purified amount of thecompound of formula (V), or a pharmaceutically acceptable salt thereof,to treat the disease or disorder.

Examples of diseases and disorders include, but are not limited to,cardiovascular disease, atrial fibrillation, blood clotting, coronaryheart disease, hypercoagulable states, ischemia, myocardial infarction,myopathy, myositis, pulmonary embolism, stroke, peripheral vasculardisease, dyslipidemia, dyslipoproteinemia, a disorder of glucosemetabolism, Alzheimer's disease, Parkinson's disease, diabeticnephropathy, diabetic retinopathy, insulin resistance, metabolicsyndrome disorders (e.g., Syndrome X), galactosemia, HIV infection, aperoxisome proliferator activated receptor-associated disorder,septicemia, a thrombotic disorder, obesity, pancreatitis, hypertension,renal disease, cancer, inflammation (e.g., liver inflammation),inflammatory muscle diseases (e.g., polymyalgia rheumatica,polymyositis, and fibrositis), impotence, gastrointestinal disease,irritable bowel syndrome, inflammatory bowel disease, inflammatorydisorders (e.g., asthma, vasculitis, ulcerative colitis, Crohn'sdisease, Kawasaki disease, Wegener's granulomatosis, (RA), systemiclupus erythematosus (SLE), multiple sclerosis (MS), and autoimmunechronic hepatitis), arthritis (e.g., rheumatoid arthritis, juvenilerheumatoid arthritis, and osteoarthritis), osteoporosis, soft tissuerheumatism (e.g., tendonitis), bursitis, autoimmune disease (e.g.,systemic lupus and erythematosus), scleroderma, ankylosing spondylitis,gout, pseudogout, non-insulin dependent diabetes mellitus, diabetes(e.g., type 2), polycystic ovarian disease, hyperlipidemias (e.g.,primary hyperlipidemia, familial hypercholesterolemia (FH),Hypercholesterolemia Frederickson Type Ha, HypercholesterolemiaFrederickson Type IIb, familial combined hyperlipidemia (FCH)),lipoprotein lipase deficiencies (e.g., hypertriglyceridemia,hypoalphalipoproteinemia, and hypercholesterolemia), lipoproteinabnormalities associated with diabetes, lipoprotein abnormalitiesassociated with obesity, and lipoprotein abnormalities associated withAlzheimer's disease. In particular embodiments, the methods includetreating and/or preventing hyperlipidemia such as primaryhyperlipidemia. In some embodiments, the methods include treating and/orpreventing cardiovascular disease.

In certain embodiments, bempedoic acid, or a pharmaceutically acceptablesalt thereof, as described and/or made herein, including apharmaceutical material and/or a pharmaceutical composition, may be usedfor the treatment or prevention of one or more of high levels of lowdensity lipoprotein cholesterol (LDL-C), high levels of apolipoprotein B(apoB), high levels of lipoprotein(a) (Lp(a)), high levels of very lowdensity lipoprotein (VLDL), high levels of non-high density lipidcholesterol (non-HDL-C), high levels of total serum cholesterol (TC),high levels of high sensitivity c-reactive protein (hsCRP), high levelsof fibrinogen, high levels of insulin, high levels of glucose, and lowlevels of high density lipoprotein cholesterol (HDL-C). In other words,methods of the invention can include lowering LDL-C, lowering apoB,lowering Lp(a), lowering VLDL, lowering non-HDL-C, lowering TC, and/orlowering hsCRP. Methods of the invention can include inhibitingadenosine triphosphate citrate lyase (ACL), inhibiting cholesterolsynthesis, and/or suppressing fatty acid biosynthesis. In someembodiments, a purified amount of the compound of formula (V), or apharmaceutically acceptable salt thereof, a pharmaceutical compositionor a pharmaceutical material of the present invention may be used as anadjunct to diet and maximally tolerated statin therapy to lower LDL-C inadults with heterozygous familial hypercholesterolemia or establishedatherosclerotic cardiovascular disease. In some embodiments, a purifiedamount of the compound of formula (V), or a pharmaceutically acceptablesalt thereof, a pharmaceutical composition or a pharmaceutical materialof the present invention may be used for the treatment of non-insulindependent diabetes mellitus without increasing weight gain.

In certain embodiments, bempedoic acid, or a pharmaceutically acceptablesalt thereof, as described and/or made herein, including apharmaceutical material and/or a pharmaceutical composition, may be usedfor the treatment or prevention of a variety of diseases and conditions,which include, but are not limited to aging, Alzheimer's disease,cancer, cardiovascular disease, diabetic nephropathy, diabeticretinopathy, a disorder of glucose metabolism, dyslipidemia,dyslipoproteinemia, enhancing bile production, hypertension, impotence,inflammation, insulin resistance, lipid elimination in bile, modulatingC reactive protein, obesity, oxysterol elimination in bile,pancreatitis, pancreatitius, Parkinson's disease, a peroxisomeproliferator activated receptor-associated disorder, phospholipidelimination in bile, renal disease, rhabdomyolysis, septicemia, sleepapnea, Syndrome X, and a thrombotic disorder.

In certain embodiments, provided herein is a method of treating a liverdisorder selected from the group consisting of steatohepatitis,alcoholic liver disease, fatty liver, liver steatosis, liver cirrhosis,liver fibrosis, and acute fatty liver of pregnancy. In some embodiments,the disorder is steatohepatitis. In some embodiments, thesteatohepatitis is nonalcoholic steatohepatitis. In some embodiments,the steatohepatitis is nonalcoholic fatty liver disease. In someembodiments, the disorder is alcoholic liver disease. In someembodiments, the disorder is fatty liver. In some embodiments, thedisorder is liver steatosis, liver cirrhosis, or liver fibrosis. In someembodiments, the disorder is acute fatty liver of pregnancy. In someembodiments, the patient is an adult human.

In certain embodiments, the present invention provides a method fortreating or preventing aging, Alzheimer's disease, cancer,cardiovascular disease, diabetic nephropathy, diabetic retinopathy, adisorder of glucose metabolism, dyslipidemia, dyslipoproteinemia,enhancing bile production, enhancing reverse lipid transport,hypertension, impotence, inflammation, insulin resistance, lipidelimination in bile, modulating C reactive protein, obesity, oxysterolelimination in bile, pancreatitis, pancreatitius, Parkinson's disease, aperoxisome proliferator activated receptor-associated disorder,phospholipid elimination in bile, renal disease, septicemia, metabolicsyndrome disorders (e.g., Syndrome X), or a thrombotic disorder.

In certain embodiments, the disorder is selected from the groupconsisting of lipodystrophy, lysosomal acid lipase deficiency, and aglycogen storage disease. In some embodiments, the patient is an adulthuman.

In certain embodiments, the disorder is selected from the groupconsisting of hepatitis C, an infection by human immunodeficiency virus,an alpha 1-antitrypsin deficiency, Bassen-Kornzweig syndrome,hypobetalipoproteinemia, Celiac disease, Wilson's disease, andWeber-Christian syndrome. In some embodiments, the disorder is hepatitisB. In some embodiments, the disorder is hepatitis C. In someembodiments, the disorder is an infection by human immunodeficiencyvirus. In some embodiments, the disorder is an alpha 1-antitrypsindeficiency. In some embodiments, the disorder is Bassen-Kornzweigsyndrome. In some embodiments, the disorder is hypobetalipoproteinemia.In some embodiments, the disorder is Celiac disease or Wilson's disease.In some embodiments, the disorder is Weber-Christian syndrome. In someembodiments, the patient is an adult human.

In certain embodiments, the condition is selected from the groupconsisting of toxic liver injury, total parenteral nutrition, severesurgical weight loss, environmental toxicity, malnutrition, andstarvation. In some embodiments, the condition is toxic liver injury. Insome embodiments, the condition is total parenteral nutrition or severesurgical weight loss. In some embodiments, the condition isenvironmental toxicity. In some embodiments, the condition ismalnutrition or starvation. In some embodiments, the patient is an adulthuman.

In certain embodiments, in order to prolong the effect of a drug, thecompound of formula (V), or a pharmaceutically acceptable salt thereof,is administered by subcutaneous or intramuscular injection, or bydissolving or suspending the drug in an oil vehicle.

In certain embodiments, the actual dosage level of the compound offormula (V), or a pharmaceutically acceptable salt thereof, in thepharmaceutical compositions of the present invention may be varied so asto obtain an amount of the compound of formula (V), or apharmaceutically acceptable salt thereof, which is effective to achievethe desired therapeutic response for a particular patient, composition,and mode of administration, without being toxic to the patient.

In certain embodiments, the selected dosage level is dependent upon avariety of factors including the route of administration, the time ofadministration, the rate of excretion or metabolism of the particularcompound being employed, the rate and extent of absorption, the durationof the treatment, other drugs, compounds and/or materials used incombination with the particular compound employed, the age, sex, weight,condition, general health and prior medical history of the patient beingtreated, and like factors well known in the medical arts.

In certain embodiments, a physician or veterinarian having ordinaryskill in the art can readily determine and prescribe the effectiveamount of the pharmaceutical composition as required.

In certain embodiments, a suitable daily dose of the compound of formula(V) or a pharmaceutically acceptable salt thereof, will be an amountthat corresponds to the lowest dose effective to produce a therapeuticeffect. In certain embodiments, the compound of formula (V), or apharmaceutically acceptable salt thereof, is administered at about 0.01mg/kg to about 200 mg/kg. In certain embodiments, when compound offormula (V), or a pharmaceutically acceptable salt thereof, isco-administered with another therapeutic agent, the effective amount maybe less than when the compound of formula (V), or a pharmaceuticallyacceptable salt thereof, is used in isolation.

In certain embodiments, the effective daily dose of the compound offormula (V), or a pharmaceutically acceptable salt thereof, may beadministered as two, three, four, five, six or more sub-doses. Incertain embodiments, the two, three, four, five, six or more sub-dosesare administered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. In some embodiments, dosing is oneadministration per day. In some embodiments, the compound of formula(V), or a pharmaceutically acceptable salt thereof, is administered to apatient for 1 day, 5 days, 10 days, 20 days, 30 days, 1 week, 2 weeks, 3weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, thecompound of formula (V), or a pharmaceutically acceptable salt thereof,is administered to a patient for the duration of the patient's lifespan.

VII. Combination Therapy

In various embodiments, bempedoic acid, or a pharmaceutically acceptablesalt thereof, as described and/or made herein, including pharmaceuticalmaterials and pharmaceutical compositions of the present invention, canbe part of a combination therapy. In certain embodiments, thecombination therapy comprises the compound of formula (V), or apharmaceutically acceptable salt thereof; and a second therapeuticagent. In certain embodiments, the combination therapy comprises apharmaceutical material comprising a purified amount of the compound offormula (V), or a pharmaceutically acceptable salt thereof; and a secondtherapeutic agent.

In some embodiments, the second therapeutic agent is selected from thegroup comprising a lovastatin, a thiazolidinedione or fibrate, abile-acid-binding-resin, a niacin, an anti-obesity drug, a hormone, anantiviral agent (e.g., to treat an underlying hepatitis C infectioncausing liver disease in the patient), anticancer agents (e.g., to treathepatocellular carcinoma or other cancer causing liver disease or fattyliver), antioxidants, medications that decrease insulin resistance, ormedications that improve lipid metabolism (e.g., treatments forhyperlipidemia), a tyrophostine, a sulfonylurea-based drug, a biguanide,an α-glucosidase inhibitor, an apolipoprotein A-I agonist,apolipoprotein E, a cardiovascular drug, an HDL-raising drug, an HDLenhancer, or a regulator of the apolipoprotein A-I, apolipoprotein A-IVand/or apolipoprotein genes. In some embodiments, the purified amount ofthe compound of formula (V), or a pharmaceutically acceptable saltthereof, is greater than 99.0% by weight of the total weight of thepharmaceutical material.

In various embodiments, the second therapeutic agent can be a statinand/or ezetimibe. See, e.g., U.S. Patent Application Publication Nos.2018/0078518 (combination of bempedoic acid with a statin), 2018/0064671and 2018/0338922 (combination of bempedoic acid with ezetimibe);International Publication No. WO 2018/218147 (combination of bempedoicacid with ezetimibe); and International Publication No. WO 2018/148417(combination of bempedoic acid with ezetimibe and a statin).

In certain embodiments, administering a pharmaceutical material or apharmaceutical composition of the present invention comprising thecompound of formula (V), or a pharmaceutically acceptable salt thereof,and a second therapeutic agent is intended to provide a beneficialeffect from the co-action of the compound of formula (V), or apharmaceutically acceptable salt thereof, and a second therapeuticagent. In some embodiments, the beneficial effect of the combinationtherapy may include pharmacokinetic or pharmacodynamic co-actionresulting from the combination of the compound of formula (V), or apharmaceutically acceptable salt thereof, and a second therapeuticagent.

VIII. Kits

In various embodiments, the invention provides kits for treating acondition, disease or disorder described herein. In some embodiments, akit comprises: i) instructions for treating a condition, disease ordisorder, for example, as described herein, and ii) the compound offormula (V), or a pharmaceutically acceptable salt thereof (e.g., apharmaceutical material comprising a purified amount of the compound offormula (V), or a pharmaceutically acceptable salt thereof). In someembodiments, the kit may comprise one or more unit dosage formscontaining an amount of the compound of formula (V), or apharmaceutically acceptable salt thereof, that is effective for treatingthe condition, disease or disorder.

The description herein includes multiple aspects and embodiments of thepresent invention, including methods of making the compound of formula(V), or a pharmaceutically acceptable salt thereof; methods of using acompound of formula (V), or pharmaceutically acceptable salt thereof,for example, a purified amount of the compound of formula (V), or apharmaceutically acceptable salt thereof; compositions comprising apurified amount of the compound of formula (V), or pharmaceuticallyacceptable salt thereof; and kits. The patent application specificallyincludes all combinations and permutations of the aspects andembodiments as described herein. In particular, it should be understoodthat the pharmaceutical materials, pharmaceutical compositions, methodsof treating a disorder or a condition, and kits can include and/or usebempedoic acid, or a pharmaceutically acceptable salt thereof, as madeby the methods described herein.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following example is set forth. The synthetic andanalytical protocols described in this application are offered toillustrate the compounds, pharmaceutical compositions, and methodsprovided herein and are not to be construed in any way as limiting theirscope.

Example 1: Manufacturing Process for Preparing a Pharmaceutical MaterialComprising a Purified Amount of the Compound of Formula (V)

In this example, the synthesis of purified bempedoic acid refers to FIG.1.

Step 1—Preparation of Compound of Formula (I) Lithium Diisopropylamide(LDA) Preparation

A reaction vessel was charged with diisopropylamine (317±3 kg, 1.1 eq.)and tetrahydrofuran (THF, 2,102±105 L) and the mixture then cooled to≤−10° C. n-Butyllithium (n-BuLi, 757±8 kg, 1.2 eq.) was then dosed over≥1 hour while the temperature was maintained at ≤−10° C. The charge linewas rinsed with THF. The addition was highly exothermic. Finally, thebatch was then cooled back to ≤−10° C. while being stirred.

Alkylation Reaction

Ethyl isobutyrate (317±3 kg, 1.1 eq.) was added to the reactor over ≥1hour at ≤−10° C. (FIG. 1). The batch was stirred while maintaining thetemperature at ≤−10° C. 1-Bromo-5-chloropentane (460±5 kg, 1.00 eq.) wasdosed over ≥1 hour at ≤−10° C. The line was rinsed with THF. Theaddition was highly exothermic. The reaction mixture was then stirredfor ≥10 hours at ≤−10° C. This stage of the reaction was confirmed to becomplete using gas chromatography (1-bromo-5-chloropentane: ≤3% area).The reaction mixture was then warmed to 0±5° C. and this temperaturemaintained until the conversion was complete. The reaction was confirmedto be complete using gas chromatography (1-bromo-5-chloropentane: <0.5%area).

Quench and Phase Separation

A solution of 9% hydrochloric acid (HCl, 1337±50 kg) was added to thereaction mixture over ≥1 hour while the temperature was maintained at≤30° C. to quench the reaction. After dosing, the reaction mixture wasstirred at ≤30° C. for ≥15 minutes. The pH of the aqueous layer wasmeasured (range: pH 6 to 10). The agitator was stopped and the layerswere allowed to settle for ≥30 minutes. The lower aqueous phase wasremoved for disposal.

Distillation and Removal of THF

The solvent was removed by distillation under vacuum at ≤40° C. to thedesired volume of approximately 950 L.

The concentration of the compound of formula (I) was measured using gaschromatography (GC) (target compound of formula (I) concentration range:57-62% wt). If necessary, to adjust the concentration of the compound offormula (I) to be within the target range, THF was added or furtherremoved via distillation.

The batch was then cooled to ≤30° C. and the crude compound of formula(I) concentrate was drummed. The process for obtaining the compound offormula (I) was repeated in an identical manner to obtain a secondbatch.

Step 2—Preparation of Compound of Formula (II) Additional Aqueous Wash

Two individual batches of the compound of formula (I) (57-62% w/wsolution in THF) were charged to a vessel. While stirring, 5% HCl(1,767±79 kg) was charged at ≤25° C. The addition was exothermic. Themixture was agitated for ≥15 minutes. Agitation was stopped and thephases were allowed to settle for ≥30 minutes. The lower aqueous phasewas removed, leaving compound of formula (I)/THF in the reactor.

Iodide Exchange Reaction

Methyl-ethyl-ketone (MEK, 4,384±227 L) and sodium iodide (NaI, 831±9 kg,1.16 eq.) were charged while stirring (FIG. 1). The batch was heated toreflux (75-80° C.). After approximately 30 hours, GC was used to measurereaction completion (compound of formula (I) <1.0% area). If thereaction had not completed, additional time was allowed (expectedreaction time: 25 to 35 hours) and NaI was recharged as needed. Themixture was then cooled to approximately 20° C.

Solvent Exchange and Aqueous Work-Up

The batch was concentrated via vacuum distillation at ≤60° C. until nomore distillate was collected. The mixture was then cooled to 20±5° C.and n-heptane (3,624±187 L) was charged. Then, 5% aqueous sodiumbisulfate (NaHSO₃, 2,121±104 kg) was added and the mixture stirred for≥60 minutes. Agitation was stopped and the phases allowed to settle for≥60 minutes. The lower aqueous phase was removed for disposal. Water(1980±102 L) was added and the mixture agitated for ≥60 minutes. Thephases were allowed to settle for ≥60 minutes and the lower aqueousphase removed for disposal. An optional second water wash was performedif required.

Final Concentration

The batch was concentrated using vacuum distillation at ≤50° C. until nomore distillate was collected. The batch was then cooled to 20° C. andthe compound of formula (II) was drummed and sampled for assay analysis.The expected yield range was 80-120% (w/w %).

Step 3—Preparation of Compound of Formula (IV)

Sodium t-Pentoxide/DMAc Preparation

The following intermediate/compound of formula (IV) sequence was basedon a charge of 700 kg of compound of formula (II)/n-heptane with assayof 94.9% wt/wt, which represented a contained charge of 665 kg ofcompound of formula (II).

A solution of N,N-dimethylacetamide (DMAc, 1,476±37 kg) and sodiumt-pentoxide (271±3 kg, 2.10 eq.) was prepared in a vessel and themixture was agitated for approximately 30 minutes until nearly all ofthe solids were dissolved.

Preparation of the First Intermediate

Compound of formula (II) (700 kg, 1 eq.), DMAc (1,272±27 kg), and TosMIC(219±1 kg) were charged to a vessel (see FIG. 1). The mixture was cooledto ≤−5° C. and well agitated. To this solution, the sodiumt-pentoxide/DMAc mixture was added over approximately 1 hour at ≤−5° C.The transfer line was rinsed with DMAc (181±9 kg). The reaction wasstrongly exothermic. The reaction mixture was agitated for ≥30 minutesat ≤−5° C. The conversion was confirmed to be complete usinghigh-performance liquid chromatography with ultraviolet detection(HPLC-UV) (monoalkylated TosMIC ≤1% area and compound of formula (II)≤1.4% area). Optional kicker charges of compound of formula (II), TosMICand sodium t-pentoxide were employed as required, to ensure completionof the reaction, based on the following instructions (Table 18):

TABLE 18 Instructions for Determining Kicker Charge Action IPC TestResult Criteria Kicker Charge Action ≤1% Monoalkylated TosMIC Chargeadditional TosMIC and and >1.4% compound of formula (II) sodiumt-pentoxide >1% Monoalkylated TosMIC Charge additional compound of and≤1.4% compound of formula (II) formula (II) >1% Monoalkylated TosMICCharge additional sodium and >1.4% compound of formula (II) t-pentoxide

Quench and Phase Separation

n-Heptane (2,407±120 L) and water (3,061±153 L) were charged to anotherreactor. The first intermediate reaction mixture was transferred to then-heptane/water mixture under temperature control between 0° C. and 40°C. (target 20° C.). The reaction was slightly exothermic. The transferline was rinsed with n-heptane (470±24 L). The mixture was then agitatedfor ≥1 hour. Agitation was stopped and the mixture allowed to settle for≥1 hour. The lower aqueous phase was removed for disposal. A solution of5% aqueous sodium chloride (NaCl, 3,106±147 kg) was charged and themixture agitated for ≥1 hour at approximately 20° C. (range: 0° C. to40° C.). The agitator was stopped and the mixture allowed to settle for≥60 minutes. The lower aqueous phase was removed for disposal. Theremaining solution of the first intermediate in n-heptane wastransferred to another vessel.

Compound of Formula (IV) Reaction

Isopropyl acetate (IPAc, 451±23 L) was added to the solution of thefirst intermediate in n-heptane and the mixture cooled to −10±10° C.Concentrated HCl (115±2 kg) was added while maintaining the temperatureat ≤25° C. The reaction was exothermic and the reaction mixture allowedto warm, if needed, to 20±5° C. The mixture was agitated for ≥30 minutesduring the warming period. The reaction conversion was measured usingHPLC-UV (intermediate ≤2% area).

Quench and Phase Separation

In a separate vessel, a sodium hydroxide (NaOH) solution (50% wt/wt,175±2 kg) was combined with water (1927±96 L). The resulting aqueousNaOH solution was added to the reaction mixture at approximately 20° C.(range: 10° C. to 40° C.). The line was rinsed with water. The mixturewas stirred for ≥3 hours. The neutralization endpoint is pH 9 to 12.Agitation was stopped and the phases allowed to settle for ≥60 minutes.The lower aqueous phase was removed for disposal. A dilute aqueoussolution, containing NaCl (55±3 kg), water (1,572±79 L) and 50% sodiumhydroxide (4.6±0.2 kg), was prepared in a separate vessel and charged tothe compound of formula (IV) product mixture. A water rinse (128±6 L)was applied and the mixture was agitated for ≥60 minutes. Agitation wasstopped and the phases were allowed to settle for ≥60 minutes. The loweraqueous phase was removed for disposal.

Concentration

The mixture was concentrated under vacuum at ≤80° C. until no moredistillate was collected. The distillation was monitored using GC(compound of formula (IV) ≥75% area). The batch was cooled toapproximately 20° C. and the compound of formula (IV) concentrate washeld until the second batch was prepared. The process for preparing thecompound of formula (IV) was repeated in an identical manner to providea second batch of the compound of formula (IV) in n-heptane. The secondbatch (in n-heptane) was then combined with the first batch for finaldistillation and packaging. The product was weighed and sampled forassay. The expected yield range is 80-120% w/w.

Step 4—Preparation of Compound of Formula (V) (Crude Bempedoic Acid)Reaction 1 (Ketone Reduction)

Compound of formula (IV) (545±5 kg) and ethanol (EtOH, 1090±55 kg) werecharged to a vessel. While maintaining the batch at ≤35° C., sodiumborohydride (NaBH₄, 12 wt % in 40% NaOH, 155±2 kg, 0.35 eq.) was chargedover approximately 2-3 hours (FIG. 1). The addition was exothermic. Thecharging line was rinsed with water (155±8 kg). After holding at 25±10°C. for ≥1 hour the conversion was measured using HPLC-UV (compound offormula (IV) ≤0.5% area).

Reaction 2 (Saponification)

An aqueous solution of NaOH (50% wt/wt, 435±4 kg) was charged to thevessel at ≤50° C. The addition was exothermic. The charging line wasrinsed with water (155±8 kg) and the reaction mixture was warmed to50±5° C. for ≥6 hours. The saponification was measured using HPLC-UV(compound of formula (V) monoester ≤0.5% area). Water (1873±94 kg) wascharged to the reaction mixture. EtOH and water were distilled undervacuum and at ≤50° C. until the batch volume reached the target level(approximately 2184 L). The mixture was transferred to another reactorand the transfer line was rinsed with water (273±14 kg).

pH Adjustment, Phase Separation, and Extraction

Methyl tert-butyl ether (MTBE, 1628±81 kg) was added and the batchcooled to 10-15° C. Concentrated HCl (647±6 kg) was added slowly at10-20° C. (the addition was exothermic) and the batch stirred ≥1 hour. Asample was taken for pH analysis and the pH was adjusted with HCl orNaOH as needed (target pH range: 5 to 6). The formation of hydrogen gaswas observed. Agitation was stopped and the phases were allowed tosettle for ≥60 minutes at 10-20° C. The lower aqueous phase was removedfor disposal. The batch was transferred to another vessel and rinsedforward with MTBE. The concentration of compound of formula (V) in MTBEwas measured using HPLC-UV (compound of formula (V): 17% to 20% weight).

Step 5—Purification of Compound of Formula (V)/Preparation ofCrystalline Form of Compound of Formula (V) Silica Gel Preparations

The diameter×height ratio for the silica gel plug varied from 1×1 to1×3. Silica gel (60±2 kg) was charged to a filter and wetted with ethylacetate (EtOAc) that was charged into the reactor and then drained tothe filter. The silica gel bed was preheated by recirculating EtOAc(1,173±59 kg) at 50±5° C. Excess EtOAc was removed immediately prior tofiltration of the compound of formula (V) batch.

Solvent Exchange to Ethyl Acetate

The compound of formula (V) in MTBE was charged to a reactor. The batchwas concentrated under vacuum at ≤50° C. to 30% to 35% of the initialvolume. EtOAc (2,002±100 kg) was charged and the batch was concentratedagain to 30% to 35% of the initial volume. EtOAc (1601±80 kg) wascharged and distillation is repeated. EtOAc (1601±80 kg) was charged andthe batch was sampled. The solvent exchange was measured by GC (MTBE≤0.1% weight). Additional EtOAc charges and distillations were performedas required.

Silica Gel Filtration

When the solvent exchange was complete, the batch was warmed to 50±5° C.Then the batch was filtered through the preheated silica gel plug intoanother reactor. To rinse the line and the silica gel, EtOAc (964±20 kg)was charged to the reactor, warmed to 50° C., and then a portion of thewarm EtOAc was transferred through the silica gel plug. Loss of productdue to retention on the silica gel filter was measured using HPLC(compound of formula (V) ≤0.5% weight in the eluate). Additional flusheswith EtOAc were performed as required. Purified compound of formula (V)in EtOAc was partially concentrated by distillation under vacuum, at≤50° C., to a final volume of approximately 1700 L.

Crystallization

The temperature of the concentrated compound of formula (V) in EtOAc wasadjusted to approximately 50±5° C. Water (24±1 kg) was charged, the linewas rinsed with EtOAc (74±10 kg) and the solution was maintained at50±5° C. for ≥1 hour. The solution was then cooled to 22±5° C. using acooling rate of 14° C./hour, with slow agitation, and then held at thistemperature for ≥2 hours to initiate crystallization. Once slurryformation was confirmed, the solution was stirred at approximately20-25° C. for ≥6 hours. The batch was then cooled to 0±5° C. using acooling rate of 11° C./hour and then stirred at this temperature for ≥6hours.

Isolation and Drying

The crude crystalline form of the compound of formula (V) was isolatedby centrifugation at 0±5° C. and then washed with chilled EtOAc at 0±5°C. The wet cake was dried under vacuum at ≤45° C. Drying was monitoredby loss-on drying (LOD) (LOD ≤0.5%).

Optional In Situ Filtration

For vessels designed with in-reactor (in situ) filtration, the slurrywas allowed to settle for ≥1 hour at 0±5° C. The batch was filtered andthe wet cake was left in the reactor. EtOAc (1,064±53 kg) was charged toanother vessel, chilled to 0±5° C. and transferred, backwards throughthe decant filters, to the reactor containing the wet cake. The batchwas agitated for ≥1 hour and then allowed to settle for ≥1 hour.Filtration was repeated. The slurry wash and filtration process wasrepeated three times in an identical manner.

Step 6—Preparation of Pharmaceutical Material Including Purified Amountof Compound of Formula (V) Recrystallization (Ethyl Acetate/Water)

Following in situ filtration, the amount of the crystalline form of thecompound of formula (V) produced in Step 5 was estimated based on theassumption that there was 100% conversion of the compound of formula(IV) (charge amount—545 kg) into the compound of formula (V) in Step 4(FIG. 1).

In a reactor, EtOAc was charged to the crystalline form of the compoundof formula (V) wetcake until the volume reaches the 1433 L mark(approximately 619 kg of EtOAc) and the suspension was then heated to55-60° C. until all solids dissolved. To the clear solution, water (16±1kg) was added and the batch agitated at 55-70° C. for ≥1 hour. Thetemperature was adjusted to 55±5° C. and the batch was then transferredto another reactor via polish filtration. The reactor, filter and linewere rinsed with EtOAc (162±12 kg). The temperature was adjusted to55±5° C. The hot solution was then cooled over ≥1 hour to 30±5° C. andagitated for ≥2 hours. The batch was then heated over ≥1 hour to 40±5°C. and then maintained at 40±5° C. for ≥1 hour. The batch was thencooled over ≥1 hour to 35±5° C. and then maintained at 35±5° C. for ≥2hours. The batch was then cooled over ≥5 hours to 5±5° C. and thenmaintained at 5±5° C. for ≥4 hours. The resulting solids were isolatedby centrifugation. The wash solvent was acetonitrile (ACN), stored foruse at 20±10° C.

Isolation, Drying, Compound Identification of the Compound of Formula(V) and IPC Testing

The purified compound of formula (V) solids were collected bycentrifugation and then washed with acetonitrile (2×2 kg/kg of thecompound of formula (V)) at 20±10° C. to remove all residual motherliquor. The wet cake was dried in vacuum at ≤45° C. Yield: 324.2 kg(84.9%) of a pharmaceutical material comprising a purified amount of thecompound of formula (V).

The purified compound of formula (V) was prepared for ¹H- and ¹³C-NMRanalysis by preparing 10 mg/mL and 50 mg/mL solutions of the purifiedcompound of formula (V) in CDCl₃. ¹H- and ¹³C-NMR spectra were obtainedusing an Inova 500 MHz NMR spectrometer. To ensure better relativequantitation of the integrals and that all signals were captured thewindow was expanded from 5000 to 8000 Hz and the wait time extendedbetween acquisitions from 1 to 25 sec. The resulting ¹H- and ¹³C-NMRspectra of the compound of formula (V) (FIGS. 2(a) and 2(b),respectively) are consistent with known ¹H- and ¹³C-NMR spectra ofbempedoic acid (Table 19).

TABLE 19 Bempedoic acid ¹H- and ¹³C-NMR assignments Signal AssignmentSignal Location (ppm) Nucleus Proton (mult) Carbon CO₂H 11.99 (singlet)179.05 C2 N/A 41.43 (CH₃)₂ 1.05 (singlet) 25.23 C3/H3 1.41 (multiplet)40.46 C4/H4 1.15-1.34 (multiplet) 24.78 C5/H5 1.15-1.34 (multiplet)29.99 C6/H6 1.15-1.34 (multiplet) 25.42 C7/H7 1.41 (multiplet) 37.39C8/H8 3.32 (singlet) 69.69 OH 4.19 (singlet) N/A

A sample of the purified compound of formula (V) was run on an Agilent1100 HPLC coupled to a Thermo LTQ-XL Mass Spectrometer electrosprayrunning in positive electrospray mode. The capillary temperature was200° C. The column was a Waters X-Bridge C18, 4.6×75 mm, 2.5 μm. Mobilephase A was 0.05% formic acid and mobile phase B was 0.04% formic acidin acetonitrile. The experimental mass of the compound of formula (V)was found to be 344.38 Da, which is in good agreement with thecalculated mass for bempedoic acid of 344.49 Da.

The expected yield range was 66-91%. The residual solvent was measuredusing GC (ACN ≤350 ppm) to determine completion of drying. When dryingwas complete, impurities were measured using HPLC with charged aerosoldetection (CAD) (unknown impurities ≤0.08% by weight and knownimpurities ≤0.13% by weight). If the impurity profile criterion was met,the product was treated as the final Active Pharmaceutical Ingredient(API). If the impurity profile criterion was not met, anotherrecrystallization was performed as described above.

Using the HPLC assay described in Example 3, the purity of the purifiedcompound of formula (V) was determined to be 99.6% (w/w).

X-ray powder diffraction (XRPD) data for the crystalline form of thecompound of formula (V) were collected using a Panalytical X'Pert³Powder diffractometer (Cu, Kα radiation; X-ray tube setting—45 kV, 40mA; divergence slit—fixed ⅛ °; scan mode—continuous; scan range—3 to 40°(2θ); scan step time—18.87 seconds; step size—0.0131° (2θ)). Samples ofthe crystalline form of the compound of formula (V) were placed on a Sizero-background holder. The 2 theta position was calibrated against aPanalytical Si reference standard disc. An XRPD pattern of thecrystalline form of the compound of formula (V) is provided in FIG. 4.Tabulated characteristics of the XRPD pattern in FIG. 4 are providedbelow in Table 20, which lists diffraction angle 2θ and relativeintensity (expressed as a percentage with respect to the most intensepeak).

Differential Scanning Calorimetry (DSC) data for the crystalline form ofthe compound of formula (V) were collected using a TA Q2000 DSCinstrument. The DSC instrument was calibrated using an indium referencestandard. Samples of the crystalline form of the compound of formula (V)were placed inside crimped aluminum sample pans and heated at a rate of10° C./minute from ambient temperature (˜25° C.) to 300° C. A DSC curvefor the crystalline form of the compound of formula (V) is provided inFIG. 5. The DSC curve displayed an endothermic event with an onset valueof about 92.4° C.

Thermogravimetric analysis (TGA) data for the crystalline form of thecompound of formula (V) were collected using a TA Discovery 550 TGAinstrument. The TGA instrument was calibrated using a nickel referencestandard. Samples of the crystalline form of the compound of formula (V)were placed in open platinum sample pans and heated at a rate of 10°C./minute from about ambient temperature (˜25° C.) to about 315° C. ATGA curve for the crystalline form of the compound of formula (V) isprovided in FIG. 6. The TGA curve displayed negligible weight loss priorto decomposition occurring.

TABLE 20 X-ray Powder Diffraction Pattern Data of the Crystalline Formof the Compound of Formula (V) Angle [2θ] Relative Intensity [%] 5.22.33 10.3 70.75 10.4 78.65 11.8 2.88 13.7 2.72 15.5 8.08 15.6 7.16 17.38.20 17.6 18.72 17.9 100.00 18.8 42.30 19.5 21.42 19.7 15.07 20.4 16.9320.7 23.95 21.1 5.78 22.0 13.87 22.6 17.54 23.1 7.78 23.6 4.97 23.9 6.1924.7 1.98 25.8 3.04 26.3 2.10 27.5 13.36 29.2 3.86 30.2 1.27 30.8 5.3431.3 1.40 31.9 2.95 32.9 1.27 34.4 5.98 35.1 2.07 36.2 3.16 37.2 2.3737.9 1.79

In addition, single crystals of the crystalline form of the compound offormula (V) were analyzed by single crystal X-ray diffraction. The unitcell parameters of the crystalline form of the compound of formula (V)and the data collection and structure refinement methods are shown inTables 21 and 22, respectively.

TABLE 21 Unit Cell Parameters of the Crystalline Form of the Compound ofFormula (V) Empirical formula C₁₉H₃₆O₅ Formula weight 344.48 Temperature297(2) K Wavelength 0.71073 Å Crystal size 0.400 × 0.140 × 0.090 mmCrystal system Monoclinic Space group P2₁/c Unit cell dimensions a =17.9209(8) Å α = 90° b = 9.8547(5) Å β = 106.8340(10)° c = 12.2775(6) Åγ = 90° Volume 2075.35(17) Å³ Z 4 Density (calculated) 1.102 Mg/m³Absorption coefficient 0.078 mm⁻¹ F(000) 760

TABLE 22 Data Collection and Structure Refinement Methods for theCrystalline Form of the Compound of Formula (V) Diffractometer Bruker D8Quest PHOTON 100 CMOS Radiation source Incoatec Microfocus Source (IμS)monochromated MoKa Data collection method omega/phi scans Theta rangefor data collection 2.384° to 25.243° Limiting indices −21 <= h <= 21,−11 <= k <= 11, −14 <= l <= 14 Reflections collected/unique 51013/3745[R(int) = 0.0514] Completeness to theta = 25.242 99.8% Absorptioncorrection Semi-empirical from equivalents Max. and min. transmission0.7454 and 0.6534 Refinement method Full-matrix least-squares on F²Data/restraints/parameters 3745/3/228 Goodness-of-fit on F² 1.027 FinalR indices [I > 2sigma(I)] R1 = 0.0684, wR2 = 0.1658 R indices (all data)R1 = 0.0858, wR2 = 0.1780 Extinction coefficient n/a Largest diff. peakand hole 0.956 and −0.379 e · A⁻³

Atomic coordinates (×10⁴) and equivalent isotropic displacementparameters (Å²×10³) are shown in Table 23, below. U(eq) is defined asone third of the trace of the orthogonalized U^(ij) tensor.

TABLE 23 Atomic Coordinates and Equivalent Isotropic Atomic DisplacementParameters for the Crystalline Form of the Compound of Formula (V) Atomx y z U(eq) O1 8702(1)  759 (2) 9437(2) 54(1) O2 7773(1)  838(2)10289(2)  61(1) O3 7792(1) 9467(2) 7690(2) 64(1) O4 3323(1) 6206(2)3606(2) 61(1) O5 3141(1) 8412(2) 3400(2) 58(1) C1 8438(2) 1070(2)10303(2)  39(1) C2 9051(1) 1748(3) 11258(2)  40(1) C3 8742(2) 1960(4)12278(2)  65(1) C4 9778(2)  833(3) 11597(3)  62(1) C5 9260(2) 3111(3)10806(2)  43(1) C6 8566(2) 4011(3) 10253(3)  50(1) C7 8782(2) 5364(3)9841(2) 53(1) C8 8072(2) 6113(3) 9111(3) 55(1) C9 8256(2) 7413(3)8618(3) 65(1) C10 7539(2) 8176(3) 7903(3) 57(1) C11 7131(2) 7409(3)6807(2) 51(1) C12 6389(2) 8053(3) 6074(2) 52(1) C13 5964(2) 7180(3)5081(3) 53(1) C14 5205(2) 7760(3) 4343(2) 49(1) C15 4828(1) 6862(3)3332(2) 44(1) C16 4040(1) 7331(3) 2540(2) 42(1) C17 3762(2) 6284(3)1581(3) 61(1) C18 4109(2) 8719(3) 2026(3) 60(1) C19 3454(1) 7401(3)3216(2) 41(1)

Bond lengths (Å) are shown in Table 24, below.

TABLE 24 Selected Bond Lengths (Å) for the Crystalline Form of theCompound of Formula (V) Bond Bond length (Å) Bond Bond length (Å)O(1)—H(1)  0.862(18) C(6)—C(7) 1.514(4) O(1)—C(1) 1.318(3) C(7)—C(8)1.519(4) O(2)—C(1) 1.209(3) C(8)—C(9) 1.494(4) O(3)—H(3)  0.910(18)C(9)—C(10) 1.528(4) O(3)—C(10) 1.400(3) C(10)—C(11) 1.532(4) O(4)—H(4) 0.859(18) C(11)—C(12) 1.512(4) O(4)—C(19) 1.318(3) C(12)—C(13) 1.507(4)O(5)—C(19) 1.197(3) C(13)—C(14) 1.511(4) C(1)—C(2) 1.511(4) C(14)—C(15)1.515(4) C(2)—C(4) 1.540(4) C(15)—C(16) 1.535(4) C(2)—C(3) 1.523(4)C(16)—C(19) 1.516(4) C(2)—C(5) 1.540(4) C(16)—C(17) 1.536(4) C(5)—C(6)1.519(4) C(16)—C(18) 1.527(4)

Bond angles (°) are shown in Table 25, below.

TABLE 25 Selected Bond Angles (°) for the Crystalline Form of theCompound of Formula (V) Bond Bond angle (°) angle (°) H(1)—O(1)—C(1) 109(2) O(3)—C(10)—C(9) 106.9(2) H(3)—O(3)—C(10)  107(2)O(3)—C(10)—C(11) 112.5(2) H(4)—O(4)—C(19)  114(3) C(9)—C(10)—C(11)111.7(3) O(2)—C(1)—O(1) 121.8(2) C(12)—C(11)—C(10) 115.4(2)O(2)—C(1)—C(2) 125.9(2) C(11)—C(12)—C(13) 113.1(2) O(1)—C(1)—C(2)112.2(2) C(12)—C(13)—C(14) 115.2(2) C(1)—C(2)—C(4) 108.6(2)C(15)—C(14)—C(13) 112.4(2) C(1)—C(2)—C(3) 110.1(2) C(14)—C(15)—C(16)117.0(2) C(4)—C(2)—C(3) 109.8(2) C(19)—C(16)—C(15) 108.8(2)C(1)—C(2)—C(5) 107.70(19) C(19)—C(16)—C(17) 109.1(2) C(4)—C(2)—C(5)109.4(2) C(15)—C(16)—C(17) 108.6(2) C(3)—C(2)—C(5) 111.2(2)C(19)—C(16)—C(18) 109.7(2) C(6)—C(5)—C(2) 114.7(2) C(15)—C(16)—C(18)111.2(2) C(7)—C(6)—C(5) 114.1(2) C(17)—C(16)—C(18) 109.4(2)C(6)—C(7)—C(8) 112.0(2) O(5)—C(19)—O(4) 122.2(2) C(7)—C(8)—C(9) 114.2(3)O(5)—C(19)—C(16) 125.3(2) C(8)—C(9)—C(10) 114.0(3) O(4)—C(19)—C(16)112.5(2)

Torsion angles (°) are shown in Table 26, below.

TABLE 26 Selected Torsion Angles (°) for the Crystalline Form of theCompound of Formula (V) Torsion Torsion angle (°) angle (°)H(1)—O(1)—C(1)—O(2)   −3(3) C(8)—C(9)—C(10)—C(11) −67.6(4)H(1)—O(1)—C(1)—C(2)  178(3) O(3)—C(10)—C(11)—C(12) −62.9(4)O(2)—C(1)—C(2)—C(4) 126.7(3) C(9)—C(10)—C(11)—C(12) 176.9(3)O(1)—C(1)—C(2)—C(4) −54.3(3) C(10)—C(11)—C(12)—C(13) −173.4(3) O(2)—C(1)—C(2)—C(3)  6.5(4) C(11)—C(12)—C(13)—C(14) 178.2(3)O(1)—C(1)—C(2)—C(3) −174.5(2)  C(12)—C(13)—C(14)—C(15) 177.3(3)O(2)—C(1)—C(2)—C(5) −114.9(3)  C(13)—C(14)—C(15)—C(16) 178.3(2)O(1)—C(1)—C(2)—C(5)  64.2(3) C(14)—C(15)—C(16)—C(19) −61.2(3)C(1)—C(2)—C(5)—C(6)  52.0(3) C(14)—C(15)—C(16)—C(17) −179.8(2) C(4)—C(2)—C(5)—C(6) 169.9(2) C(14)—C(15)—C(16)—C(18)  59.7(3)C(3)—C(2)—C(5)—C(6) −68.7(3) H(4)—O(4)—C(19)—O(5)    4(3)C(2)—C(5)—C(6)—C(7) 178.4(2) H(4)—O(4)—C(19)—C(16)  −176(3)C(5)—C(6)—C(7)—C(8) 169.7(2) C(15)—C(16)—C(19)—O(5) 116.1(3)C(6)—C(7)—C(8)—C(9) −176.1(3)  C(17)—C(16)—C(19)—O(5) −125.6(3) C(7)—C(8)—C(9)—C(10) −178.9(3)  C(18)—C(16)—C(19)—O(5)  −5.8(4)H(3)—O(3)—C(10)—C(9)  −174(2) C(15)—C(16)—C(19)—O(4) −63.2(3)H(3)—O(3)—C(10)—C(11)   63(2) C(17)—C(16)—C(19)—O(4)  55.1(3)C(8)—C(9)—C(10)—O(3) 168.9(3) C(18)—C(16)—C(19)—O(4) 174.9(2)

Anisotropic Displacement Parameters (Å²) are shown in Table 27, below.The anisotropic displacement factor exponent may be expressed in theform: −2π²[h²a*²U¹¹+ . . . +2 h k a*b*U¹²].

TABLE 27 Anisotropic Displacement Parameters (Å²) for the CrystallineForm of the Compound of Formula (V) Atom U11 U22 U33 U23 U13 U12 O152(1) 60(1) 48(1) −18(1)  13(1) −4(1)  O2 48(1) 70(1) 70(1) −12(1) 23(1) −12(1)  O3 70(1) 38(1) 67(1) −1(1) −7(1) 3(1) O4 67(1) 40(1) 92(2)12(1) 47(1) 7(1) O5 57(1) 39(1) 83(2)  0(1) 26(1) 10(1)  C1 44(1) 31(1)42(1)  4(1) 12(1) 5(1) C2 44(1) 42(1) 32(1)  3(1)  6(1) 4(1) C3 76(2)80(2) 39(2)  3(2) 17(2) 0(2) C4 56(2) 60(2) 61(2) 14(2)  1(1) 15(2)  C543(1) 40(1) 39(1) −2(1)  1(1) −3(1)  C6 52(2) 44(2) 55(2)  6(1) 15(1)6(1) C7 61(2) 37(2) 50(2) −1(1) −4(1) −2(1)  C8 61(2) 40(2) 59(2)  4(1)10(1) 5(1) C9 63(2) 36(2) 74(2)  8(1) −14(2)  −9(1)  C10 54(2) 44(2)60(2)  8(1) −3(1) −6(1)  C11 49(2) 36(1) 59(2)  0(1)  1(1) 0(1) C1248(2) 44(2) 57(2) −4(1)  3(1) 1(1) C13 45(2) 47(2) 59(2) −8(1)  5(1)3(1) C14 44(2) 44(2) 55(2) −6(1)  8(1) 2(1) C15 40(1) 40(1) 54(2) −7(1)15(1) 0(1) C16 39(1) 40(1) 45(1) −2(1) 11(1) −4(1)  C17 60(2) 67(2)55(2) −16(2)  16(1) −13(2)  C18 62(2) 55(2) 63(2) 14(2) 16(2) −6(2)  C1935(1) 36(1) 48(2) −1(1)  7(1) 2(1)

Hydrogen atom coordinates and isotropic atomic displacement parameters(Å²) are shown in Table 28, below.

TABLE 28 Hydrogen Atom Coordinates and Isotropic Displacement Parameters(Å²) for the Crystalline Form of the Compound of Formula (V) Atom x y zU H(1) 8339(16) 350(30) 8930(20) 81(12) H(3) 7357(15) 9950(30) 7330(30)85 H(4) 2972(18) 6210(40) 3960(30) 90(13) H(3B) 9136 2391 12880 97 H(3C)8287 2525 12061 97 H(3D) 8610 1098 12537 97 H(4A) 10173 1252 12205 93H(4B) 9642 −32 11845 93 H(4C) 9973 708 10953 93 H(5A) 9609 3604 11434 52H(5B) 9541 2928 10255 52 H(6A) 8224 3531 9611 60 H(6B) 8277 4176 1079760 H(7A) 9146 5214 9403 64 H(7B) 9039 5921 10493 64 H(8A) 7725 6306 956966 H(8B) 7795 5522 8494 66 H(9A) 8594 7218 8147 78 H(9B) 8541 7997 923478 H(10A) 7171 8278 8352 68 H(11A) 7493 7322 6357 62 H(11B) 7010 65007009 62 H(12A) 6516 8915 5790 63 H(12B) 6046 8235 6540 63 H(13A) 58586307 5370 63 H(13B) 6305 7021 4609 63 H(14A) 4848 7873 4799 59 H(14B)5302 8648 4073 59 H(15A) 4758 5967 3616 53 H(15B) 5189 6770 2881 53H(17A) 4131 6235 1151 91 H(17B) 3718 5410 1904 91 H(17C) 3262 6552 109091 H(18A) 4480 8671 1599 90 H(18B) 3610 8983 1531 90 H(18C) 4279 93762624 90

Selected hydrogen bond information (Å and °) shown in Table 29, below.

TABLE 29 Selected Hydrogen Bond Formation (A and °) for the CrystallineForm of the Compound of Formula (V) D-H . . . A d(D-H) d(H. . . A) d(D .. . A) <(DHA) O(1)—H(1) . . . O(3) #1 0.862(18) 1.78(2) 2.618(3) 165(3)O(3)—H(3) . . . O(5) #2 0.910(18) 1.94(3) 2.768(3) 151(3) O(4)—H(4) . .. O(2) #3 0.859(18) 1.87(2) 2.716(3) 168(4)Symmetry transformations used to generate equivalent atoms: #1 x,y−1,z#2−x+1,−y+2,−z+1 #3−x+1,y+½,−z+3/2

Example 2: Alternative Manufacturing Process for Preparing aPharmaceutical Material Comprising a Purified Amount of the Compound ofFormula (V) Step 1—Preparation of Compound of Formula (I) LithiumDiisopropylamide (LDA) Preparation

A reaction vessel was charged with approximately 321 kg ofdiisopropylamine and approximately 1870 L of tetrahydrofuran (THF) andthe mixture was then cooled to −18° C. to −5° C. Approximately 794 kg ofn-butyllithium (n-BuLi, solution in heptane) was slowly dosed whilemaintaining the temperature at −18° C. to −5° C. The batch was held to−18° C. to −5° C. with stirring.

Alkylation Reaction

Approximately 317 kg of ethyl isobutyrate was added to the reactorcontaining the LDA over a target ≥1 hour with the temperature controlledat −18° C. to −5° C. The line was then rinsed with approximately 100 LTHF. The batch was stirred while maintaining the temperature at −18° C.to −5° C. Approximately 460 kg of 1-bromo-5-chloropentane was dosed overa target ≥1 hour at −18° C. to −5° C. The line was then rinsed withapproximately 100 L THF. The reaction mixture was stirred at −18° C. to−5° C. and then warmed to 0° C.±5° C. The reaction was confirmed to becomplete using gas chromatography (GC) (1-bromo-5-chloropentane: ≤0.4%area).

Quench and Phase Separation

Approximately 1337 kg of a solution of 9% aqueous hydrochloric acid(HCl) was added to the reaction mixture while maintaining thetemperature at ≤30° C. to quench the reaction. After dosing, thereaction mixture was stirred at 20° C.±5° C. for ≥15 minutes. The layersare allowed to settle. The pH of the aqueous layer was then measured(range: pH 6 to 10). If the pH range is not met, additional sodiumhydroxide (NaOH) or HCl may be added. The lower aqueous phase wasremoved for disposal.

Distillation and Removal of THF

The solvent was removed by distillation under vacuum at ≤40° C. to thedesired volume of approximately 950 L.

The crude compound of formula (I) concentrate was temporarily stored ina reaction vessel or drummed until processing continues to make thecompound of formula (II). The compound of formula (I) process wasrepeated in an identical manner to obtain a second batch.

Step 2—Preparation of Compound of Formula (II) Additional Aqueous Wash

Two individual batches of the compound of formula (I) in THF are chargedto a vessel. While stirring, approximately 1767 kg of a 5% aqueous HClsolution was then charged at 20° C.±5° C. The mixture was agitated for≥15 minutes. Agitation was stopped, and the phases were allowed tosettle. The lower aqueous phase was removed, leaving the compound offormula (I)/THF in the reactor.

Iodide Exchange Reaction

Approximately 4386 L of methyl-ethyl-ketone (MEK) and approximately 824kg of sodium iodide (NaI) were charged while stirring. The batch washeated to reflux. After approximately 30 hours, GC was used to measurereaction completion (the compound of formula (I) ≤3.0% area). If thereaction has not completed, additional time is allowed and additionalNaI may be charged if needed. The mixture was then cooled toapproximately 20° C.±10° C.

Solvent Exchange and Aqueous Work-Up

The batch was concentrated via vacuum distillation at ≤60° C. until nomore distillate was collected. Approximately 3000 L of n-heptane wasthen charged. Approximately 2115 kg of 5% aqueous sodium bisulfite(NaHSO₃) was prepared and the compound of formula (II) reaction mixturewas added. An n-heptane rinse of approximately 612 L was charged. Themixture was stirred at 20° C.±5° C. Agitation was stopped, and thephases were allowed to settle. The lower aqueous phase was removed fordisposal. About 1976 L of water was added, the mixture was agitated, thephases were allowed to settle, and the lower aqueous phase was thenremoved for disposal. The water wash was repeated one more time.

Final Concentration

The batch was concentrated using vacuum distillation at ≤50° C. until nomore distillate was collected. The compound of formula (II) was thendrummed and sampled for intermediate testing. The expected yield rangeis 80% to 100%.

Step 3—Preparation of Compound of Formula (IV)

Sodium t-Pentoxide/DMAc Preparation

The following first intermediate/compound of formula (IV) sequence isbased on a charge of approximately 722 kg of compound of formula(II)/heptane with assay of 90.0% wt/wt, which represents a containedcharge of 650 kg of compound of formula (II).

A solution of approximately 1450 kg of N, N-Dimethylacetamide (DMAc) andapproximately 267.3 kg of sodium t-pentoxide was prepared in a vesseland the mixture agitated at ≤30° C.

Preparation of First Intermediate

The compound of formula (II) in heptane (approximately 722 kg), DMAc(approximately 1259 kg), and TosMIC (approximately 213.8 kg) werecharged to a vessel. The mixture was then cooled to −15° C. to 0° C. andthe mixture well agitated. To this solution, the sodium t-pentoxide/DMAcmixture was added while at −15° C. to 0° C. The transfer line was rinsedwith approximately 178 kg DMAc. The reaction mixture was agitated at−15° C. to 0° C. The conversion was confirmed to be complete usinghigh-performance liquid chromatography (HPLC) with ultraviolet detection(HPLC-UV) (monoalkylated TosMIC ≤3.0% area and compound of formula (II)≤3.0% area). Optional kicker (additional) charges of the compound offormula (II), TosMIC, and sodium t-pentoxide can be employed asrequired, to ensure completion of the reaction, based on the informationpresented in Table 30.

TABLE 30 Optional Kicker Charges for Preparation of Intermediate IPCTest Result Criteria Kicker Charge Action ≤3.0% Monoalkylated TosMICCharge additional TosMIC and >3.0% compound of formula (II) and sodimnt-pentoxide >3.0% Monoalkylated TosMIC Charge additional compound and≤3.0% compound of formula (II) of formula (II) >3.0% MonoalkylatedTosMIC Charge additional sodium and >3.0% compound of formula (II)t-pentoxide IPC = In-process control; TosMIC = p-Toluenesulfonylmethylisocyanide.

Quench and Phase Separation

Approximately 2344 L of n-heptane and approximately 2993 L of water werecharged to another reactor. The first intermediate reaction mixture wastransferred to the heptane/water mixture under temperature controlbetween 0° C. and 40° C. (target 20° C.). The transfer line was thenrinsed with approximately 456 L n-heptane. The mixture was agitated for1 to 3 hours while between 0° C. and 40° C. Agitation was then stopped,and the mixture allowed to settle. The lower aqueous phase was removedfor disposal. Approximately 3036 kg of a solution of about 5% aqueoussodium chloride (NaCl) was charged and the mixture agitated. Theagitator was then stopped, and the mixture allowed to settle. The loweraqueous phase was removed for disposal.

Compound of Formula (IV) Reaction

Approximately 440 L of isopropyl acetate (IPAc) was added to thesolution of the first intermediate in heptane and the mixture cooled to−15° C. to 0° C. Concentrated HCl (approximately 112 kg) was then addedwhile maintaining the temperature at −15° C. to 25° C. The reactionmixture was allowed to warm, if needed, to 10° C. to 25° C. The mixturewas agitated for 30 to 60 minutes once 10° C. to 25° C. was reached. Thereaction conversion was measured using HPLC-UV (the first intermediate≤20% area).

Quench and Phase Separation

In a separate vessel, approximately 177 kg of NaOH (50% wt/wt,) wascombined with about 1884 L of water. The resulting aqueous NaOH solutionwas then added to the reaction mixture at approximately 20° C. (range:10° C. to 40° C.). The line was rinsed with approximately 124 L water.The mixture was stirred. The neutralization endpoint is pH 9 to 12.Agitation was stopped, and the phases allowed to settle. The loweraqueous phase was removed for disposal. A dilute aqueous solution,containing about 54 kg of NaCl, about 1535 L of water, and about 4.5 kgof 50% NaOH, was prepared in a separate vessel and charged to thecompound of formula (IV) product mixture. A water rinse of approximately126 L was then applied. The mixture was agitated, the phases weresettled, and the lower aqueous phase removed for disposal.

Concentration

The mixture was concentrated under vacuum at ≤80° C. to a reducedvolume. The batch was then cooled to approximately 20° C. and thecompound of formula (IV) concentrate held until the second batch wasprepared. The compound of formula (IV) process was repeated in anidentical manner to provide a second batch of compound of formula (IV)in heptane. The second batch (in heptane) was then combined with thefirst batch for final distillation. The distillation was monitored usingGC (compound of formula (IV) ≥75% weight). The packaging of product wasperformed. The product was weighed and sampled for intermediate testing.The expected yield range is 85% to 105%.

Step 4—Preparation of Compound of Formula (V) (Crude Bempedoic Acid)Reaction 1 (Ketone Reduction)

Approximately 710 kg the compound of formula (IV) and approximately 1420kg ethanol (EtOH) were charged to a vessel. While maintaining the batchat 25° C.±10° C., approximately 202 kg sodium borohydride (NaBH₄, 12 wt% in 40% NaOH, approximately 0.35 eq.) was charged. The charging linewas then rinsed with approximately 202 kg water. After holding at 25°C.±5° C. for ≥1 hour the conversion was measured using HPLC-UV (compoundof formula (IV) ≤0.9% area).

Reaction 2 (Saponification)

Approximately 567 kg of a solution of NaOH (50% wt/wt) is charged at 15°C. to 50° C. The charging line is rinsed with approximately 202 kgwater, and the reaction mixture is warmed at 50° C.±5° C. for ≥6 hours.The saponification is measured using HPLC-UV (compound of formula (V)monoethyl ester ≤1.3% area). Approximately 2440 kg water is charged tothe reaction mixture. EtOH and water are distilled under vacuum and at≤50° C. until the batch volume reaches the target level (approximately2845 L).

pH Adjustment, Phase Separation, and Extraction

The mixture was diluted with approximately 356 L of water and 2121 kgmethyl tert-butyl ether (MTBE) was then added while maintaining thebatch at 15° C. to 50° C. The batch was cooled to 10° C. to 20° C.Concentrated HCl (approximately 912 kg) was added slowly at 10° C. to20° C. A sample was taken for pH analysis and the pH was adjusted withHCl or NaOH as needed (target pH range: 5.0 to 6.0). Agitation wasstopped, and the phases allowed to settle. The lower aqueous phase wasremoved for disposal. The concentration of the compound of formula (V)in MTBE was measured using HPLC-UV. The batch was then transferred toanother vessel and rinsed forward with approximately 629 kg of MTBE.

Step 5—Purification of Compound of Formula (V)/Preparation ofCrystalline Form of Compound of Formula (V) Silica Gel Preparations

The diameter×height ratio for the silica gel plug can vary from 1×0.8 to1×3. Approximately 78 kg of silica gel was charged to a filter. Thesilica gel bed was prepared by recirculating approximately 1173 kg ofEtOAc at 50° C.±5° C. Excess EtOAc was removed immediately prior tofiltration of the compound of formula (V) batch.

Solvent Exchange to Ethyl Acetate

The compound of formula (V) in MTBE was concentrated under vacuum at≤50° C. to approximately 1148 L. Approximately 2608 kg of EtOAc wascharged and the batch was then concentrated again to approximately 1148L. Approximately 2086 kg of EtOAc was charged and distillation repeated.EtOAc (approximately 2086 kg) was charged and the batch was thensampled. The solvent exchange was measured with GC (MTBE ≤0.1% weight).Additional EtOAc charges and distillations may be performed ifnecessary.

Silica Gel Filtration

When the solvent exchange was complete, the batch was warmed to 45° C.to 55° C. Then the batch was filtered through the preheated silica gelplug into another reactor. To rinse the line and the silica gel,approximately 521 kg of EtOAc was charged to the reactor, warmed to 50°C.±5° C., and then warm EtOAc was transferred through the silica gelplug. The purified compound of formula (V) in EtOAc mixture was thenpartially concentrated by distillation under vacuum, at ≤50° C., to afinal volume of approximately 2321 L.

Crystallization

The concentrated compound of formula (V) in EtOAc was adjusted toapproximately 50° C.±5° C. Approximately 31.3 kg of water was charged,and the solution was maintained at 50° C.±5° C. for ≥1 hour. Thesolution was then slowly cooled to 22° C.±5° C., with agitation, over ≥2hours to start the crystallization of the compound of formula (V). Themixture was stirred at approximately 22° C.±5° C. for ≥6 hours and thenslurry formation confirmed. If a slurry is not present, additionalstirring at 20° C. to 25° C. and seeding may be performed if necessary.The batch was then slowly cooled to 0° C.±5° C. over ≥2 hours andstirred for ≥6 hours at 0° C.±5° C.

Optional In Situ Filtration

For vessels designed with in-reactor (in situ) filtration, the slurrywas allowed to settle at approximately 0° C. The batch was thenfiltered, and the wet cake left in the reactor. Approximately 1386 kg ofEtOAc was charged to another vessel, chilled to 0° C.±5° C. andtransferred to the reactor containing wet cake. The batch was agitatedat 0° C.±5° C. and then allowed to settle. The solids were filtered. Theslurry wash and filtration processes were repeated 3 times in anidentical manner.

Step 6—Preparation of Pharmaceutical Material Including Purified Amountof Compound of Formula (V) Recrystallization (Ethyl Acetate/Water)

Following in situ filtration, the amount of the compound of formula (V)is assumed to be approximately 488 kg, based on 100% conversion of thecompound of formula (IV) charge amount (710 kg) used to prepare thecompound of formula (V).

In a reactor, EtOAc was charged to the compound of formula (V) solidsuntil the volume reaches the 1867 L mark and the suspension was thenheated to 55° C. to 60° C. with stirring. To the mixture, approximately20.5 kg of water was added, and the batch agitated at 55° C. to 70° C.for ≥1 hour. A check for the formation of a solution was performed. Thebatch was then transferred to another reactor via polish filtration. Thereactor, filter, and line were rinsed with EtOAc. The temperature wasthen adjusted to 55° C.±5° C. The hot solution was then cooled over ≥2hours to 30° C.±5° C. and then agitated at 30° C.±5° C. for ≥2 hours. Ifa slurry was not present, additional stirring at 30° C.±5° C. andseeding may be performed as required. The batch was then heated to 40°C.±5° C., over ≥1 hour and held at 40° C.±5° C. for ≥1 hour. The batchwas then cooled to 35° C.±5° C. for over ≥1 hour and held at 35° C.±5°C. for ≥2 hours. The batch was then cooled slowly over ≥5 hours to 5°C.±5° C. and held at 5° C.±5° C. for ≥4 hours.

Isolation, Drying, and IPC Testing

The resulting solids were isolated by centrifugation and washed with≤2000 kg acetonitrile. The wet cake was then dried under vacuum at ≤45°C. (jacket). The residual solvent was measured using GC (ACN ≤410 ppmand EtOAc ≤5000 ppm) to determine completion of drying. The expectedyield range is 66% to 91%. If the pharmaceutical material releasespecification criteria were met, the product was treated as the finalpharmaceutical material. If the pharmaceutical material releasespecifications were not met, a second recrystallization was conducted.

Optional Second Recrystallization (Ethyl Acetate/Water)

The following procedure describes the second recrystallization of thecompound of formula (V) for a batch size of approximately 430 kg.

Compound of formula (V) solids (approximately 430 kg) were charged to avessel, followed by EtOAc (approximately 1238 kg). The suspension wasthen heated to 55° C. to 60° C. with stirring. To the mixture,approximately 18 kg of water was added, and the mixture was thenagitated at 55° C. to 70° C. for ≥1 hour. A check for the formation of asolution was performed. The temperature was then adjusted to 55° C.±5°C. and the batch transferred to another reactor via polish filtration.The reactor, filter, and line were rinsed with EtOAc and the temperaturethen adjusted to 55° C.±5° C. The hot solution was then cooled over ≥2hour to 30° C.±5° C. and then agitated at 30° C.±5° C. for ≥2 hours. Ifa slurry was not present, additional stirring at 30° C.±5° C. andseeding may be performed as required. The batch was then heated to 40°C.±5° C., over ≥1 hour and held at 40° C.±5° C. for ≥1 hour. The batchwas then cooled to 35° C.±5° C. for over ≥1 hour and held at 35° C.±5°C. for ≥2 hours. The batch was then cooled slowly over ≥5 hours to 5°C.±5° C. and held at 5° C.±5° C. for ≥4 hours.

Optional Isolation, Drying, and IPC Testing

The resulting solids were isolated by centrifugation and washed with≤2000 kg acetonitrile. The wet cake was dried under vacuum at ≤45° C.(jacket). The residual solvent was then measured using GC (ACN ≤410 ppmand EtOAc ≤5000 ppm) to determine completion of drying. The expectedyield range is 75% to 100%. If the impurity profile criteria were met,the product is treated as the final pharmaceutical material.

Example 3: Analytical Method for Determining the Purity of the Compoundof Formula (V) Determining the Amount of Impurities

The amount of impurities present in the purified form of the compound offormula (V) was determined using a high performance liquid chromatographequipped with gradient capability, a thermostatic column compartment anda charged aerosol detection (CAD) detector.

The amount of impurities within the purified form of the compound offormula (V) was determined to be in the range of 0.05-0.50% w/w.

Column: Waters XBridge BEH C18 (4.6 mm i.d.×150 mm, 2.5 μm)

Mobile Phase: A: 0.05% Formic acid (HCOOH) in water (H₂O)Mobile Phase: B: 0.05% HCOOH in acetonitrile (ACN)Sample temperature: AmbientColumn temperature: 40° C.Gradient (time: A:B): (0 min: 90:10; 8.5 min., 56:44; 20 min, 45:55; 32min., 5:95; 36 min., 5:95).Flow rate: 1.2 mL/minRetention time: ˜15.2 min (purified form of bempedoic acid)

Determining the Purity of the Compound of Formula (V) (Bempedoic Acid)

The level of purity of the purified form of the compound of formula (V)was determined using a high performance liquid chromatograph equippedwith a UV detector.

The assay for the purified form of the compound of formula (V) wasdetermined to be in the range of 98-102% (anhydrous, solvent-freebasis).

Column: Waters XBridge BEH C18 (4.6 mm i.d.×150 mm, 2.5 μm)

Mobile Phase: A: 0.05% Phosphoric acid (H3PO4) in H₂O:ACN (50:50)Sample temperature: AmbientColumn temperature: 40° C.

Detection: 215 nm

Flow rate: 1.2 mL/minAnalysis time: 16 min.

Gradient: Isocratic

Retention time: ˜4.6 min (purified form of bempedoic acid)

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

1-38. (canceled)
 39. A pharmaceutical material comprising a crystallineform of the compound of formula (V):

or a pharmaceutically acceptable salt thereof; wherein thepharmaceutical material comprises the compound of formula (V), or apharmaceutically acceptable salt thereof, in an amount greater than99.0% by weight based on the total weight of the pharmaceuticalmaterial.
 40. The pharmaceutical material of claim 39, wherein thecrystalline form of the compound of formula (V) exhibits an X-ray powderdiffraction pattern comprising peaks at the following diffraction angles(2θ): 10.3±0.2, 10.4±0.2, 17.9±0.2, 18.8±0.2, 19.5±0.2, and 20.7±0.2.41. The pharmaceutical material of claim 39, wherein the crystallineform of the compound of formula (V) is characterized by the followingX-ray powder diffraction pattern expressed in terms of diffraction angle2θ: Angle [2θ] 5.2 10.3 10.4 11.8 13.7 15.5 15.6 17.3 17.6 17.9 18.819.5 19.7 20.4 20.7 21.1 22.0 22.6 23.1 23.6 23.9 24.7 25.8 26.3 27.529.2 30.2 30.8 31.3 31.9 32.9 34.4 35.1 36.2 37.2 37.9


42. The pharmaceutical material of claim 39, wherein the crystallineform of the compound of formula (V) exists in a monoclinic crystalsystem and has a P2₁/c space group.
 43. The pharmaceutical material ofclaim 42, wherein the crystalline form of the compound of formula (V) ischaracterized by the following crystallographic unit cell parameters:Unit cell a = 17.9209(8) Å α = 90° dimensions b = 9.8547(5) Å β =106.834(10)° c = 12.2775(6) γ = 90° Volume 2075.35 Å³ Z 4 Density 1.102Mg/m³ (calculated)


44. The pharmaceutical material of claim 39, wherein the crystallineform of the compound of formula (V) is characterized by an X-ray powderdiffraction pattern substantially the same as shown in FIG.
 4. 45. Thepharmaceutical material of claim 39, wherein the crystalline form of thecompound of formula (V) has a melting point onset as determined bydifferential scanning calorimetry in the range of from about 90° C. toabout 94° C.
 46. The pharmaceutical material of claim 45, wherein thecrystalline form of the compound of formula (V) has a melting pointonset as determined by differential scanning calorimetry at about 92° C.47. The pharmaceutical material of claim 39, wherein the crystallineform of the compound of formula (V) has a differential scanningcalorimetry curve substantially the same as shown in FIG.
 5. 48. Thepharmaceutical material of claim 39, wherein the pharmaceutical materialcomprises the compound of formula (V) in an amount greater than 99.5% byweight based on the total weight of the pharmaceutical material.
 49. Thepharmaceutical material of claim 39, wherein the pharmaceutical materialcomprises the compound of formula (V) in an amount greater than 99.7% byweight based on the total weight of the pharmaceutical material.
 50. Thepharmaceutical material of claim 39, wherein the pharmaceutical materialcomprises the compound of formula (V) in an amount greater than 99.9% byweight based on the total weight of the pharmaceutical material.
 51. Thepharmaceutical material of claim 39, wherein the pharmaceutical materialcomprises the compound of formula (V) in an amount of from about 98% toabout 102% by weight based on the total weight of the pharmaceuticalmaterial, as determined by a high performance liquid chromatography(HPLC) assay.
 52. The pharmaceutical material of claim 51, wherein theHPLC assay uses a Waters XBridge BEH C18 column (4.6 mm i.d.×150 mm, 2.5μm) at a temperature of about 40° C., with isocratic elution of a mobilephase comprising about 0.05% phosphoric acid in water/acetonitrile(about 50:50) at a flow rate of about 1.2 mL/minute, and detection at215 nm, wherein the retention time of the compound of formula (V) isabout 4.6 minutes.
 53. The pharmaceutical material of claim 39, furthercomprising a compound of formula (VI):

or a pharmaceutically acceptable salt thereof.
 54. The pharmaceuticalmaterial of claim 53, wherein the pharmaceutical material comprises thecompound of formula (IX), or a pharmaceutically acceptable salt thereof,in an amount no greater than about 0.15% by weight based on the totalweight of the pharmaceutical material.
 55. The pharmaceutical materialof claim 53, further comprising a compound of formula (VII):

or a pharmaceutically acceptable salt thereof.
 56. The pharmaceuticalmaterial of claim 55, wherein the pharmaceutical material comprises thecompound of formula (VII), or a pharmaceutically acceptable saltthereof, in an amount no greater than about 0.15% by weight based on thetotal weight of the pharmaceutical material.
 57. The pharmaceuticalmaterial of claim 53, further comprising less than or equal to 0.2% byweight of unknown impurities.
 58. A pharmaceutical formulationcomprising: the pharmaceutical material of claim 39; and apharmaceutically acceptable excipient. 59-61. (canceled)